REVIEW www.jasn.org

Sirtuins in Renal Health and Disease

Marina Morigi, Luca Perico, and Ariela Benigni

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Bergamo, Italy

ABSTRACT 1 Sirtuins belong to an evolutionarily conserved family of NAD -dependent deacety- heart and brain, is one of the main organs lases that share multiple cellular functions related to proliferation, DNA repair, mi- susceptible to age-related diseases, translat- tochondrial energy homeostasis, and antioxidant activity. Mammalians express ing into increased vulnerability to CKD in seven sirtuins (SIRT1–7) that are localized in different subcellular compartments. the elderly population.7 In this review, we Changes in sirtuin expression are critical in several diseases, including metabolic will focus on the biologic function of var- syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin ious sirtuins and address their role in renal is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflamma- physiology and pathophysiology. tion, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regu- SIRTUIN LOCALIZATION AND lating renal physiology. This review also details progress made in understanding the MOLECULAR TARGETS effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, high- lighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. Sirtuins 1–7 are NAD1-dependent de- In this context, the current pharmacologic approaches to enhancing the activity of acetylases (Figure 1) that regulate his- SIRT1 and SIRT3 will be discussed. tone proteins at specificlysineresidues, promoting post-translational modifi- J Am Soc Nephrol 29: ccc–ccc, 2018. doi: https://doi.org/10.1681/ASN.2017111218 cation that results in chromatin silenc- ing and transcriptional repression.5,6 Nonhistone proteins are also targets Two decades ago, studies on Saccharo- laboratories, have cast doubts on the as- for deacetylation that leads to the mod- myces cerevisiae indicated that among sumption of the role of sirtuins in longevity ulation of their activity.5,6 The depen- 2 dence of sirtuins on the cellular levels of the family of silent information regula- in these species. 1 – the coenzyme NAD links sirtuin ac- tor (Sir) genes, Sir2 was essential for In mammals, seven sirtuins (SIRT1 1 transcription silencing and DNA repair. SIRT7) constitute an evolutionarily con- tivity to energy metabolism.8 NAD is The corresponding protein product Sir2 served family of enzymes involved in produced by two biologically distinct 1 was identified as a NAD -dependent diverse yet interrelated physiologic pathways. The de novo synthesis uses histone deacetylase responsible for chro- processes with much broader enzymatic the essential amino acid tryptophan, matin silencing and the regulation of activity than deacetylases, such as ADP- supplied by dietary intake, which is me- 1 tabolized to form biosynthetic precur- yeast lifespan. Sir2 inactivation trans- ribosyl-transferases, demalonylase, and 1 lated into a proaging phenotype, whereas desuccinylase, which all require coupling sors generating NAD .Thiscofactor 1 is also recycled by the salvage path- its overexpression promoted increased with NAD (Figure 1). Unlike in worms 1 yeast lifespan, which was attributed to the and flies, studies performed in mice to way, where NAD is resynthesized ability of Sir2 to suppress the progressive deal with sirtuin’slifespanextension accumulation of self-replicating extrachro- effect have shown promising progress. mosomal recombinant DNA circles, a ma- Sirtuins have emerged as critical modu- Published online ahead of print. Publication date jor contributor to accelerated aging in lators of metabolic adaptive responses to available at www.jasn.org. yeast.2 Four and five sirtuins, showing the stress and their activities have been asso- Correspondence: Dr. Marina Morigi, IRCCS - Istituto di highest homology with yeast Sir2, were ciated with multiple diseases, including Ricerche Farmacologiche Mario Negri, Centro Anna Maria fi Astori, Science and Technology Park Kilometro Rosso, Via subsequently identi ed as longevity factors metabolic abnormalities, neurodegener- Stezzano 87, 24126 Bergamo, Italy. Email: marina.morigi@ in nematodes3 and flies,4 respectively4; ative disorders, cardiovascular diseases, marionegri.it although controversial results, possibly and cancer, all of which are age-associated Copyright © 2018 by the American Society of because of technical disparities between conditions.5,6 The kidney, along with the Nephrology

J Am Soc Nephrol 29: ccc–ccc, 2018 ISSN : 1046-6673/2907-ccc 1 REVIEW www.jasn.org

Figure 1. Sirtuins have broad enzymatic activities. (A) SIRT1, 2, 3, 5, 6, and 7 exhibit a lysine deacetylation activity of target proteins, in 1 which the coenzyme NAD is consumed to generate nicotinamide (NAM) and 29-O-acetyl-ADP-ribose (29-OAADPr). (B) SIRT4 exclusively 1 carries out ADP-ribosyl transferase activity, using NAD as the donor of the ADP-ribose group to the target proteins. ADP-ribosyl 1 transferase activity is shared with SIRT6. (C) SIRT5 uses NAD as a cofactor to demalonylate and desuccinylate target proteins, generating NAM and 29-O-malonyl-ADP-ribose (29-OMADPr) and 29-O-succinyl-ADP-ribose (29-OSADPr), respectively.

from nicotinamide by nicotinamide Despite sharing a common cofactor to factors (FoxO),17 results in reduced cell phosphoribosyltransferase (NAMPT).8 boost deacetylase activity, the functional apoptosis and senescence.15,16 SIRT1 1 NAD is a hydride acceptor that forms differences between sirtuins are greater also regulates the activity and expression the reduced dinucleotide NADH, and than their similarities, as highlighted by of hypoxia-inducible factor-2a,whichis their ratio regulates redox balance in en- their localization in distinct intracellular responsible for the hypoxic induction of 1 ergy production.8 Furthermore, NAD compartments and their broad range of erythropoietin by renal cells.18 From a 1 is the precursor for NADP and NADPH, target proteins. metabolic point of view, SIRT1 binds which preserve cells from reactive oxy- to and represses genes regulated by gen species (ROS).8 As described ele- Nuclear Sirtuins PPAR-g after food withdrawal19 and gantly in a recent review,8 after persistent SIRT1 is the most studied sirtuin, and also controls gluconeogenesis20 and mi- oxidative stress, overactivation of ADP- resides in the nucleus and regulates tochondria biogenesis by deacetylating/ ribosyltransferases (also named PARPs) both nucleosome histone acetylation activating PGC-1a.21 1 consumes NAD to promote the repair and the activity of several transcriptional As for other nuclear sirtuins, SIRT6 of ROS-induced DNA lesions,9 ulti- factors.13 Actually, SIRT1 inhibits deacetylates lysines 9 and 56 of histone mately reducing sirtuin activity.10,11 TNFa-dependent transactivation of H3 to maintain genome stability and 1 Likewise, the bioavailability of NAD NF-kB, limiting the expression of several telomere function.22 Recently, it has can also be affected by other enzymes, proinflammatory genes.14 After DNA been shown that SIRT6, in response to such as ADP-ribosyl cyclases, which damage and oxidative stress, SIRT1-de- oxidative stress, is recruited to the sites of 1 hydrolyze NAD to ADP-ribose and pendent deacetylation of p53,15,16 as well DNA double-strand breaks, promoting nicotinamide.12 as forkhead box type O transcription its repair via ADP-ribosylation.23 Thus,

2 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc,2018 www.jasn.org REVIEW the evidence that acetylation of histone pathways and detoxification through de- the balance of electrolytes and acid–base H3K56 is increased in multiple types of acetylation and activation of SOD2, favor- homeostasis, reabsorbing nutrients, and cancer24 suggests that SIRT6 plays a role ing superoxide discharge.43,44 In addition, BP control. Given their role as privileged in the process of tumor suppression. SIRT3 activates isocitrate dehydrogenase 2, sensors of the metabolic state of the cell, SIRT7 is the only sirtuin located in an enzyme that promotes the restoration of renal sirtuins are involved in the above nucleoli, where its deacetylase activity antioxidants and catalyzes a key step of the physiologic processes, supporting the pro- is required for ribosomal DNA tran- tricarboxylic acid cycle.45,46 Other meta- duction of sufficient energy throughout scription. A recent report proposes bolic processes directly and indirectly the different tubular and glomerular com- there is direct interaction between related to the tricarboxylic acid cycle are partments. In terms of activity, proximal SIRT7 and chromatin remodeling com- controlled by SIRT3 via the deacetylation tubules reabsorb .80% of the glomerular plexes to regulate RNA polymerase of acetyl-CoA synthase 247 and glutamate filtrate, which is supported by active trans- I transcriptional activity.25 It has been dehydrogenase,35 involved in glutamate/ port mechanisms, and therefore contain also reported that SIRT7 deacetylates glutamine metabolism,48 which fuels the more mitochondria than distal tubules several modulators of nuclear-encoded urea cycle. Moreover, SIRT3 promotes and collecting ducts.59 At the glomerular mitochondrial genes, such as GABPb1, b-oxidation by driving long-chain acyl level, podocytes require energy to adapt which favors mitochondrial oxidative CoA dehydrogenase activity,49 and ketone their highly interconnected cytoskeletal phosphorylation,26 and the nuclear re- body generation by promoting the deacety- proteins to environmental changes, thus ceptors TR4/TAK1, which are involved lation of 3-hydroxy-3-methylglutaryl CoA maintaining an intact glomerular filtra- in lipid metabolism.27 synthase 2.50 tion barrier.60 Below, we discuss the avail- Mitochondrial SIRT4 is predomi- able data on the functional activity of Cytoplasmic Sirtuins nantly an ADP-ribosylase and has the SIRTs 1, 3, 6, and 7 and their specifictar- SIRT2 is the unique cytoplasmic sirtuin opposite effects to SIRT3, in that it inac- gets in the different compartments of the that colocalizes and deacetylates a-tubu- tivates the enzymes involved in the urea kidney (Figure 2). lin,28 taking part in the microtubule- cycle48 and b-oxidation,51 but induces In the kidney, SIRT1 is widely ex- related mitotic exit from the cell cycle.29,30 lipogenesis through malonyl CoA decar- pressed in tubular cells and podocytes. Moreover, SIRT2, by inhibiting caspase-3 boxylase deacetylation.51 Notably, that The abundance of SIRT1 expression, and ROS generation, affects apoptosis and SIRT4 governs the cellular metabolic re- also in aquaporin 2-positive cells in the oxidative stress.31 The involvement of sponse to DNA damage via glutamine rat distal nephron, has been taken to sug- SIRT2 in cell metabolism has been suppor- metabolism inhibition would suggest it gest that it is possibly involved in sodium ted by data that SIRT2 is instrumental in has a role as a tumor suppressor.52 More and water handling.61 SIRT1 decreases AKT activation by insulin,32 as well as in recently, SIRT4 has been shown to play a epithelial sodium reabsorption by in- regulating FOXO1 and PCG-1a deacety- crucial role in insulin secretion and glu- teracting with methyl transferase, the lation in adipocytes.33,34 cose homeostasis, as demonstrated by disruptor of telomeric silencing-1, ulti- the development of glucose intolerance mately repressing the transcription of Mitochondrial Sirtuins and insulin resistance in SIRT4-deficient the a-subunit of the epithelial sodium SIRT3localizesinthemitochondrialmatrix mice.53 channel (ENaC) in cultured inner med- and is the major regulator of the whole SIRT5 was initially described as a mi- ullary collecting duct cells.61 The inhib- organelle acetylome, unlike other mito- tochondrial deacetylase that regulates the itory effect of SIRT1 on the promoter of chondrial sirtuins such as SIRT4 and urea cycle through the direct activation of ENaC is independent of its deacetylase SIRT5.35 Within the mitochondrial elec- carbamoyl phosphate synthetase 1.54 activity.61 The capacity of SIRT1 to reg- tron transport chain, SIRT3 directly binds Subsequent studies have revealed that ulate sodium and water handling in the to and regulates complex I, succinate SIRT5 also exhibits demalonylase and kidney might ultimately affect BP. In this dehydrogenase A of complex II, and ATP desuccinylase activities, through which context, data are also available to synthase (complex V), thus powerfully it controls ketogenesis.55,56 An impor- indicate a counterregulatory role of boosting ATP levels.36–38 During mem- tant effect of SIRT5 as an inducer of SIRT1 on renin-angiotensin system acti- brane depolarization, SIRT3 dissociates the energetic flux via glycolysis has also vation. Overexpression of SIRT1 down- fromcomplexVandinducesrapiddeace- been shown.57 regulates angiotensin II type 1 receptor tylation of specificclustersofmatrixpro- (AT1R) in vascular smooth muscle teins to optimize energy production.39 cells,62 whereas the reduced expression SIRT3 controls energy production in man- SIRTUINS IN RENAL PHYSIOLOGY of SIRT1 is associated with the increased 63 ifold ways, as it also manages the molecular transcription of AT1Rinpodocytes. machinery that governs mitochondrial dy- The kidney is one of the main energy- These findings, together with the evi- namics40,41 and permeability.42 Concomi- demanding organs in the human dence that SIRT1 upregulates endothelial tantly, SIRT3 plays a major-role in the body,58 primarily because of its role in nitric oxide synthase, points to SIRT1 as a regulation of mitochondrial antioxidant incessantly filtering blood, regulating potential player in BP control.64

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Figure 2. Sirtuins contribute to maintain renal homeostasis and thei downregulation leads to chronic and acute kidney diseases. (A) Sirtuins are expressed throughout the different renal compartments. In the glomerulus (inset), SIRT1, SIRT3, and SIRT6 maintain the structural and functional integrity of podocytes. In close proximity to podocytes, glomerular endothelial cells express SIRT1, which controls systemic BP by regulating endothelial nitric oxide synthase (eNOS). SIRT1 is also ubiquitously expressed throughout all of the nephron segments and participates in sodium balance control and water reabsorption by regulating the a-subunit of the epithelial sodium channel (ENaC) in aquaporin 2-positive cells of the distal nephron. SIRT1 and SIRT3 are highly expressed in the proximal tubule, where they preserve mitochondrial functional integrity. In the collecting duct, SIRT7 controls acid–base and renal electrolyte handling through 1 2 its ability to deacetylate the K /Cl cotransporter KCC4. (B) SIRT1, SIRT3, and SIRT6 exerts protective functions by modulating several renal targets (light blue). Downregulation of SIRT1, SIRT3, and SIRT6 favors the development of renal disorders (blue). BCL2, B cell lymphoma 2; DRP1, Dynamin related protein 1; FOXO4, Forkhead box protein O4; GSK3b,glycogensynthasekinase3b; KIF5c, kinesin family member 5C; MMP-14, matrix metalloproteinase 14; OPA1, Optic atrophy 1; p53, tumor protein 53; PGC1-a, peroxisome pro- liferative activated receptor g coactivator 1-a; Smad 3/4, Small mothers against decapentaplegic 3/4; STAT3, signal transducer and activator of transcription 3.

SIRT3 is likely to have a major role in mitochondrial network to dilute oxi- that experience remarkable glomerular the kidney. Compelling evidence corre- dized proteins and ROS, favoring sus- injury, specifically in podocytes, consist- latesSIRT3activity with the maintenance tained energy production.40 In this ing of decreased slit diaphragm protein of mitochondrial energy homeostasis context, SIRT3 has been described as a expression and foot process efface- and antioxidant defense in proximal crucial regulator of the mitochondrial ment.68 That SIRT6 is a key enzyme in and distal tubule compartments. De- dynamics in renal cells (Figure 3), tip- the maintenance of glomerular permse- pending on the renal-specificenergyde- ping the balance toward fusion.41 More lectivity to plasmatic proteins and podo- mand, mitochondria are able to modify recently, a novel role of SIRT3 in the reg- cyte function is also supported by data their size, number, and location.65,66 Mi- ulation of proximal tubular cell homeo- showing that Sirt6 deletion accelerates re- tochondria are highly mobile organelles stasis has been documented. SIRT3 has nal hypertrophy and the progression of that exist in a dynamic network whose been described as controlling microtu- proteinuria.68 Finally, it has been reported function relies on complex molecular bule network-dependent trafficking of that SIRT7, through its ability to deacety- 1 2 machinery, finely tuned and balanced functional mitochondria between renal late the K /Cl cotransporter KCC4, ex- between fission and fusion.40 Fission tubular epithelial cells (Figure 3), a pro- pressed at the basolateral membrane of creates smaller mitochondria that are cess that preserves the proper cellular the a-intercalated cells, restores pH bal- more susceptible to membrane depolar- bioenergetic profile and antioxidant ance in the collecting duct compartments ization and oxidative damage and can defense.67 during metabolic acidosis.69 The positive easily be removed by mitophagic ma- The contribution of SIRT6 to govern- effect of SIRT7 on KCC4 suggests this sir- chinery.40 Conversely, fusion elicits the ing renal homeostasis has recently been tuin has a role in acid–base and renal elec- generation of a more interconnected demonstrated in Sirt6-deficient mice trolyte handling.69

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Figure 3. SIRT3 preserves the integrity of mitochondria and their intercellular shuttling between renal cells. Graphic representation depicting the functional activities of SIRT3 in the maintenance of proximal tubular epithelial cellhomeostasis.Inphysiologic conditions (left), SIRT3 controls the global functional and structural integrity of mitochondria by sustaining ATP production and the activity of the antioxidant enzyme SOD2. This enables the constitutive trafficking of healthy organelles along the intact tubulin network via the anterograde motor protein Kif5c (left inset). After tubular cell injury (right), SIRT3 downregulation resulted in a remarkable ATP depletion, as well as im- pairment of SOD2 antioxidant activity. The downregulation of SIRT3 expression and activity also translates into unbalanced mitochondrial dynamics toward fission and fragmentation (right inset) by priming Drp1 recruitment on the mitochondrial outer membrane by binding to its receptor MFF, as well as reducing OPA1 expression. In association with fragmentation, loss of mitochondrial membrane permeability drives the disposal of dysfunctional organelles through PINK1-dependent mitophagy. The upregulation of SIRT3 expression and activity through pharmacologic manipulation with AICAR or ALCAR, as well as cell-based therapy with MSCs, counteracts mitochondrial dys- function and restores the cell-cell exchange of healthy organelles between injured tubular cells. AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; ALCAR, acetyl-L-carnitine; Drp1, Dynamin related protein 1; Kif5c, kinesin family member 5C; DCm, mitochondrial membrane potential; MMF, mitochondrial fission factor; OPA1, Optic atrophy 1; PINK1, PTEN-induced putative kinase 1.

SIRTUINS IN RENAL DISEASES play a crucial role in AKI after an ische- mice from cisplatin-induced AKI by en- mic or toxic challenge.71,73 Central to hancing medium chain acyl-CoA dehy- Given the growing knowledge of the role tubular damage is the dysregulation of drogenase, the rate-limiting enzyme of of sirtuins in renal physiology, several mitochondria, which shift their dy- mitochondrial b-oxidation.77 Con- attempts have been made to elucidate namic equilibrium toward fission and versely, one-allele genetic depletion of the effect they have on the development fragmentation coupled with membrane Sirt1 significantly aggravates renal func- of renal disorders. Of the seven sirtuins, depolarization and the consequent tion decline as well as tubular damage we will focus mainly on SIRT1 and leakage of proapoptotic factors.40,74 and apoptosis in a model of AKI induced SIRT3, for which data on both chronic The impairment of mitochondrial by ischemia–reperfusion injury.78 Fur- and acute kidney diseases are available. structural integrity ultimately results ther studies show that SIRT1 activates As for SIRT1, which has been described in ATP breakdown and ROS generation, PGC-1a, an important driver of reno- extensively,70 we will only address the leading to cytoskeletal changes, the dis- protection in AKI,79 which leads to mostly recent discoveries. ruption of cell-matrix and cell-cell in- proximal tubule repair by activating mi- teractions, and tubular epithelial cell tochondrial biogenesis and respiration AKI apoptosis and loss.40,74 via oxidative phosphorylation.80 AKI is a public health concern associated A large body of literature describes the In addition to SIRT1, recent studies with high mortality, the development of renal protective effects of SIRT1 in AKI, have also highlighted the renoprotective long-term CKD and other types of organ mainly because of its activity on mito- activity of SIRT3 in counteracting mito- dysfunction in a considerable percentage chondrial function.75,76 Tubular cell– chondrial dysfunction in AKI.41 Mice of patients.71,72 Tubular epithelial cells targeted SIRT1 overexpression protects with cisplatin-induced AKI have severe

J Am Soc Nephrol 29: ccc–ccc, 2018 Role of Sirtuins in the Kidney 5 REVIEW www.jasn.org mitochondrial damage associated with effect of SIRT3 induced by umbilical provide in vitro data showing that prox- oxidative stress and decreased levels of cord-derived MSCs rests on the sirtuin’s imal tubular cells exposed to high glu- SIRT3 in the proximal tubular compart- ability to promote the transfer of mito- cose concentration secrete less of the ment.41 Moreover, silencing Sirt3 in chondria between adjacent tubular cells nicotinamide mononucleotide that low- mice administered cisplatin results in via tubulin-rich protrusions, so as to in- ers SIRT1 in podocytes and upregulates more severe AKI and premature death, duce global metabolic reprogramming claudin-1 expression.94 The evidence of compared with their wild-type litter- of damaged cells to sustain the energy reduced SIRT1 expression in both tubu- mates.41 The preservation of tubular supply (Figure 3).67 lar cells and glomeruli from patients SIRT3 expression and activity by AICAR, with DN provides additional clues re- an AMPK agonist, or the antioxidant Diabetic Nephropathy garding the potential involvement of agent acetyl-l-carnitine, protects SIRT3- Diabetic nephropathy (DN) is recog- SIRT1 in human DN.95,96 competent mice from renal function nized as a leading cause of ESRD world- Concerning SIRT3, there is little data impairment induced by cisplatin, but wide, as well as being an independent to support the hypothesis that it has a role has no effect in SIRT3-knockout risk factor for cardiovascular diseases in DN. Increased expression of SIRT3 mice.41 Mechanistically, proximal tubu- that contributes to morbidity and mor- antagonizes high glucose–induced cellu- lar cell dysfunction induced by cisplatin tality in patients with diabeties.86,87 In lar senescence via the FOXO1 signaling is conceivably the result of remarkable search of new therapeutic targets to pre- pathway97 and enhances cellular resis- SIRT3 reduction that primes the recruit- vent DN, the attention of the scientific tance to oxidative stress damage.98 Con- ment of the fission protein Drp1 on mi- community has turned to the role of sir- sistently, in mice with DN, the activation tochondrial membranes, as well as the tuins in diabetic complications.88 The of SIRT3 through the G protein–coupled downregulation of the pro-fusion dyna- protective effects of SIRT1 agonists on bile acid receptor prevents oxidative min-related protein OPA1, ultimately some metabolic parameters, such as glu- stress and lipid accumulation.99 The tipping mitochondrial dynamics toward cose tolerance, fasting blood glucose lev- restoration of renal SIRT3 protein ex- fission and fragmentation (Figure 3).41 els, and insulin resistance resulting in a pression and ketogenesis via green tea This process results in mitochondrial prolongation of animal lifespan, have polyphenols in rats with high fat diet– membrane permeability loss and the been described in several experimental induced DN have recently been de- elimination of the organelles through models of diabetes.89–91 Beside its ben- scribed as limiting early renal oxidative PINK-dependent mitophagy.41 Further eficial effect on the metabolism, SIRT1 damage.100 supporting the hypothesis regarding the has a protective role in limiting podo- renoprotective activity of SIRT3, a recent cyte injury in DN. There are data that Fibrosis and Aging study shows that curcumin, a natural confirm that the conditional deletion of Regardless of the etiology, renal fibrosis compound that modulates SIRT3 levels, Sirt1 in the podocytes of diabetic db/db is the hallmark of the final outcome prevents alterations in mitochondrial ul- mice results in acetylation of the p65 of almost all progressive CKDs.101 The trastructure, energy production, redox subunit of NF-kBandSTAT3,which role of SIRT1 in counteracting renal fi- balance, and dynamics in mice with likely translates into increased levels of brosis has been demonstrated in Sirt1- AKI.81 The SIRT3 biologic relevance urinary protein excretion and more se- deficient mice with unilateral ureteral in AKI has been further proved by vere renal damage compared with db/db obstruction (UUO), which display in- the renoprotective effect of potential mice without the genetic deletion.92 creased susceptibility to oxidative stress SIRT3-activator compounds such as Consistently, the downregulation of and exuberant renal apoptosis and fi- honokiol, silybin, resveratrol, and stan- SIRT1 expression is functionally linked brosis compared with their wild-type niocalcin.82–85 to FOXO4 hyperacetylation and the in- littermates.102 In this model, the use of The compelling evidence that mesen- duction of the proapoptotic factor SIRT1 activators, such as SRT1720103 chymal stromal cells (MSCs) accelerate Bcl2L11 in both injured podocytes in and SRT2183,102 substantially attenu- renal regeneration in mice with AKI has culture and glomeruli of db/db mice ates renal fibrotic processes. Conversely, created further interest in investigating with DN.93 It has been suggested that the sirtuin inhibitor sirtinol, given to whether this effect was mediated complex functional interplay between mice with UUO-induced renal fibrosis, by boosting SIRT3-dependent biologic proximal tubules and glomeruli coordi- abolishes the renoprotective effect of pathways.67 Treatment with human um- nated by SIRT1 primes DN.94 The tar- losartan, suggesting SIRT1 has a role bilical cord-derived MSCs in mice with geted disruption of SIRT1 in proximal in mediating the antifibrotic effect of AKI regulates mitochondrial biogenesis tubules of DN mice results in ectopic angiotensin II blockers.104 in proximal tubules by enhancing PGC- expression of the tight junction protein Several studies show the inverse rela- 1 1a expression, NAD biosynthesis, claudin-1 in podocytes, an event that tionship between SIRT1 and the TGFb and SIRT3 activity fostering antioxidant leads to albuminuria and renal function signaling pathway in renal fibrosis.105–107 defense and ATP production.67 The impairment.94 In search of a potential The profibrotic activity of TGFb is exerted mechanism underlying the favorable explanation for such results, the authors through the acetylation of Smad3 and 4,

6 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc,2018 www.jasn.org REVIEW in turn promoting the transcription of SIRT3’s ability to deacetylate KLF15, a andregenerativemechanisms.The natural extracellular matrix proteins and metal- negative regulator of extracellular matrix extension of these discoveries has been to loproteinases. In the UUO and 5/6 ne- protein synthesis, in cultured podo- look for sirtuin-activating compounds phrectomy models, both characterized cytes.113 (STACs; Table 1). Most STACs belong to by robust expression of TGFb, boosting Interstitial fibrosis is a unifying path- the polyphenol family of natural products, SIRT1 via both resveratrol or its agonist ologic feature of aging across several tis- of which resveratrol was the first discov- SRT3025 reduced renal inflammation, sues, contributing to the progressive ered compound capable to increase SIRT1 as well as collagen IV and fibronectin deterioration of organ functions. The almost ten-fold.123,124 Resveratrol is accumulation through the deacetylation kidney is one of the typical targets found in red wine and acts as allosteric of Smad3.105,106 Furthermore, SIRT1 affected by age-related diseases, translat- modulator, causing a conformational overexpression in tubular cells halts the ing to greater susceptibility to CKD in the change of the substrates, which increases progression of AKI to tubulointerstitial elderly population.7 Experimental evi- their binding affinity for sirtuins.124 Al- fibrosis and the consequent renal accu- dencepointstosirtuinsaskeyplayers though resveratrol’s mechanism of activa- mulation of matrix metalloproteinase-7 in counteracting age-related kidney tion was quickly disputed,125 the interest via deacetylation of Smad4.107 damage. In this context, decreased in this compound has not subsided be- AnadditionalmechanismlinkingSIRT1 SIRT1 activity observed in the kidneys cause of its caloric restriction mimetic ef- to fibrosis is provided by data showing that of aged rodents114,115 is associated with fect. This has generated several phase one 1 endothelial Sirt1 deficiency enhances peri- loss of intracellular NAD pool and in- and two clinical trials with encouraging tubular capillary rarefaction108 and perpe- creased mitochondrial dysfunction.116 results in diabetes, cardiovascular disease, trates nephrosclerosis, attributable to the Moreover, mice with podocyte-specific and neuropathy.126 Many of these studies downregulation of matrix metalloprotei- Sirt1 knockdown exhibit accelerated are the driving force behind the search for nase-14.109 These results, together with age-related albuminuria and glomerulo- natural compounds that could modulate the evidence that SIRT1 also exerts its anti- sclerosis.117 Also, SIRT3 expression de- sirtuins, such as flavonoids, stilbenes, an- fibrotic function through PGC-1a,110 in- creases in kidney specimens of aged thocyanidins, and chalcones. These mol- dicate that SIRT1 is a possible therapeutic mice.118 Conversely, renal upregulation ecules served as templates to guide the target in the progression of fibrotic kidney of SIRT3 and NAMPT, the rate-limiting computational search and chemical de- 1 diseases. The finding that SIRT1 mRNA enzyme in the biosynthesis of NAD ,as sign of more potent and specificsynthetic levels are lower in kidney biopsies obtained well as the increased number of mito- STACs, able to selectively enhance sirtuin from patients with focal glomerulosclerosis chondria are essential to the longevity deacetylase activity. Such a drug discovery adds translational relevance of the above phenotype observed in mice lacking approach has already been undertaken for data to human fibrosis.106 At1r.119 More recently, the involvement SIRT1, leading to the synthesis of different So far, the available evidence points of SIRT6 has been described as attenuat- agents such as SRT1720,103 SRT2183,102 to a protective role of SIRT3 against fi- ing age-associated renal injury through and SRT3025,106 which have been dem- brosis mainly in the heart,111,112 and the inhibition of proinflammatory NF- onstrated to limit kidney injury. As for there is little data for the kidney.112 kB signaling.120 The activation of sirtuins SIRT3, honokiol has been shown to exert SIRT3-deficient mice develop more through caloric restriction,121 supple- anti-inflammatory and antioxidant activ- 1 heart and renal fibrosis than their aged- mentation with the NAD precursor115 ity in experimental chronic and acute kid- matched wild-type littermates as they or by a SIRT1 activator122 are successful ney diesases82,113 by selectively activating age.112 Heart fibrosis in Sirt3-deficient strategies for limiting susceptibility to kid- SIRT3.127 1 animals is the result of the induction of ney injury. Compounds that boost NAD as nico- TGFb expression and the activation of its tinamide riboside and nicotinamide mono- 1 signaling.112 Whether this mechanism nucleotide, or exogenous NAD constitute could also operate in the kidney is cur- CONCLUSIONS AND FUTURE a newer class of STACs that have been rently unknown. A recent study has PERSPECTIVES found to be beneficial in cardiac and renal shown that lack of SIRT3 aggravates hy- diseases because of their ability to restore pertension-induced renal fibrosis pro- Mammalian sirtuins have emerged as a the redox balance in the setting of disrupted moted by angiotensin II infusion, whereas class of metabolic regulators that link pro- bioenergetics.8,126 Of great interest for the the overexpression of SIRT3 attenuates tein acetylation to energy metabolism, ex- future would be the development of phar- angiotensin II–induced hypertensive ne- erting renoprotective effects, as discussed macologic strategies to target enzymes that 1 phropathy.113 In addition, honokiol, a in this brief review. Although our under- regulate NAD biosynthesis, such as major bioactive compound isolated from standing of different sirtuin functions at NAMPT, as has recently been shown in Magnolia officinalis that increases SIRT3, the renal level is still in its early stages, AKI.41 In a similar vein, compounds that 1 suppresses angiotensin-induced renal fi- several advances have been made in inhibit NAD -depleting enzymes, as brosis in mice.113 The mechanism under- identifying a broad spectrum of sirtuin shown for the ADP-ribosyl cyclases in lying renoprotection has been ascribed to targets involved in cell cytoprotective multiple aged organs,128 could be another

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Table 1. Therapeutic approaches to enhance expression and activity of sirtuins in kidney diseases Compound Target Biologic Effects Experimental Models Reference Natural STACs Resveratrol SIRT1 Protects renal mitochondrial function by reducing acetylated Sepsis-associated AKI 84 SIRT3 SOD2 and oxidative stress, and prolongs animal survival Curcumin SIRT3 Ameliorates renal function and tubular damage, preserving Cisplatin-induced AKI 81 mitochondrial bioenergetics, redox balance and dynamics Silybin SIRT3 Improves renal function and reduces tubular necrosis and cell Cisplatin-induced AKI 83 apoptosis, preserving mitochondrial functions Stanniocalcin SIRT3 Reduces renal damage by activating AMPK and UCP2 IRI 85 Honokiol SIRT3 Decreases tubular damage and improves animal survival reducing Sepsis-associated AKI 82 oxidative stress, NF-kB signaling, and inflammatory cytokines SIRT3 Attenuates angiotensin II-induced renal function impairment and Hypertensive nephropathy 116 fibrosis by decreasing KLF15-dependent extracellular matrix protein expression Synthetic STACs SRT1720 SIRT1 Inhibits tubular endoplasmic reticulum stress via SIRT1-dependent UUO 103 increase of HO-1 and thioredoxin, thus slowing renal fibrosis SRT2183 SIRT1 Reduces fibrosis and apoptosis in renal medulla UUO 102 SRT3025 SIRT1 Attenuates proteinuria and GFR decline, thus reducing Remnant kidney 106 glomerulosclerosis and tubulointerstitial fibrosis NAD1-boosting therapies NMN SIRT1 Protects young and old mice from AKI; preserves renal function Cisplatin-induced AKI and IRI 115 and reduces tubular damage and apoptosis by enhancing mitochondrial density AICAR SIRT3 Ameliorates renal function and tubular damage, preserving Cisplatin-induced AKI 41 mitochondrial dynamics through the activation of AMPK signaling, NAMPT, and PGC-1a Alternative strategies CR SIRT1 Ameliorates renal function and tubular damage by reducing Cisplatin-induced AKI 121 apoptosis and preserving mitochondrial function MSCs SIRT3 Stimulates renal tubular repair by preserving functional integrity Cisplatin-induced AKI 67 of mitochondria and their exchange among tubular cells AMPK, 59 AMP-activated protein kinase; UCP2, uncoupling protein 2; IRI, ischemia–reperfusion injury; KLF15, Krüppel-like factor 15; HO-1, heme oxygenase 1; NMN, nicotinamide mononucleotide; AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; PGC-1a, peroxisome proliferator-activated receptor g coactivator 1- a; CR, caloric restriction. potential therapeutic approach. Given that M.M., L.P., and A.B. gathered data for the longevity in Saccharomyces cerevisiae by sirtuins can be considered good candidate article, contributed substantially to discus- two different mechanisms. Genes Dev 13: – targets for preventing and treating age-as- sion of the article’s content, and wrote the 2570 2580, 1999 3. Burnett C, Valentini S, Cabreiro F, Goss M, sociated disorders, including renal diseases, manuscript. Somogyvári M, Piper MD, et al.: Absence of and possibly for improving the human life- L.P. is the recipient of a fellowship from effects of Sir2 overexpression on lifespan in span, efforts to prove that sirtuin activators Fondazione Aiuti per la Ricerca sulle Malattie C. elegans and Drosophila. Nature 477: are of benefitforpatientswouldhavealarge Rare, Bergamo, Italy. 482–485, 2011 impact on clinical and public health. 4. Frankel S, Ziafazeli T, Rogina B: dSir2 and longevity in Drosophila. Exp Gerontol 46: DISCLOSURES 391–396, 2011 None. 5. Guarente L: Franklin H. Epstein lecture: ACKNOWLEDGMENTS Sirtuins, aging, and medicine. NEnglJMed 364: 2235–2244, 2011 REFERENCES 6. Haigis MC, Sinclair DA: Mammalian sirtuins: The authors are deeply indebted to Pro- Biological insights and disease relevance. fessor Giuseppe Remuzzi for his extremely Annu Rev Pathol 5: 253–295, 2010 1. Imai S, Armstrong CM, Kaeberlein M, valuable critical insights and thought- 7. Shiels PG, McGuinness D, Eriksson M, Guarente L: Transcriptional silencing and lon- Kooman JP, Stenvinkel P: The role of epi- ful suggestions. The authors also thank gevity protein Sir2 is an NAD-dependent his- genetics in renal ageing. Nat Rev Nephrol Dr. Antonella Piccinelli for helping to tone deacetylase. Nature 403: 795–800, 2000 13: 471–482, 2017 prepare the figures and Kerstin Mierke for 2. Kaeberlein M, McVey M, Guarente L: The 8. Hershberger KA, Martin AS, Hirschey MD: 1 editing the manuscript. SIR2/3/4 complex and SIR2 alone promote Role of NAD and mitochondrial sirtuins in

8 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc,2018 www.jasn.org REVIEW

cardiac and renal diseases. Nat Rev Nephrol 22. Tennen RI, Chua KF: Chromatin regulation mitochondrial deacetylase Sirt3 in regulat- 13: 213–225, 2017 and genome maintenance by mammalian ing energy homeostasis. Proc Natl Acad Sci 9. Rouleau M, Patel A, Hendzel MJ, Kaufmann SIRT6. Trends Biochem Sci 36: 39–46, 2011 USA105: 14447–14452, 2008 SH, Poirier GG: PARP inhibition: PARP1 and 23. Lerrer B, Gertler AA, Cohen HY: The com- 37. Finley LWS, Haas W, Desquiret-Dumas V, beyond. Nat Rev Cancer 10: 293–301, plex role of SIRT6 in carcinogenesis. Carci- Wallace DC, Procaccio V, Gygi SP, et al.: 2010 nogenesis 37: 108–118, 2016 Succinate dehydrogenase is a direct target 10. Bai P, Cantó C, Oudart H, Brunyánszki A, 24. Das C, Lucia MS, Hansen KC, Tyler JK: CBP/ of sirtuin 3 deacetylase activity. PLoS One 6: Cen Y, Thomas C, et al.: PARP-1 inhibition p300-mediated acetylation of histone H3 e23295, 2011 increases mitochondrial metabolism through on lysine 56. Nature 459: 113–117, 2009 38. Rahman M, Nirala NK, Singh A, Zhu LJ, SIRT1 activation. Cell Metab 13: 461–468, 25. Tsai Y-C, Greco TM, Boonmee A, Miteva Y, Taguchi K, Bamba T, et al.: Drosophila Sirt2/ 2011 Cristea IM: Functional proteomics estab- mammalian SIRT3 deacetylates ATP syn- 11. Cantó C, Sauve AA, Bai P: Crosstalk be- lishes the interaction of SIRT7 with chro- thase b and regulates complex V activity. J tween poly(ADP-ribose) polymerase and matin remodeling complexes and expands Cell Biol 206: 289–305, 2014 sirtuin enzymes. Mol Aspects Med 34: its role in regulation of RNA polymerase I 39. Yang W, Nagasawa K, Münch C, Xu Y, 1168–1201, 2013 transcription. Mol Cell Proteomics 11: 60– Satterstrom K, Jeong S, et al.: Mitochondrial 12. Graeff R, Liu Q, Kriksunov IA, Kotaka M, 76, 2012 sirtuin network reveals dynamic SIRT3-de- Oppenheimer N, Hao Q, et al.: Mechanism 26. Ryu D, Jo YS, Lo Sasso G, Stein S, Zhang H, pendent deacetylation in response to of cyclizing NAD to cyclic ADP-ribose by Perino A, et al.: A SIRT7-dependent acety- membrane depolarization. Cell 167: 985– ADP-ribosyl cyclase and CD38. JBiolChem lation switch of GABPb1 controls mito- 1000.e21, 2016 284: 27629–27636, 2009 chondrial function. Cell Metab 20: 856–869, 40.ZhanM,BrooksC,LiuF,SunL,DongZ: 13. Vaquero A, Scher M, Lee D, Erdjument- 2014 Mitochondrial dynamics: Regulatory mech- Bromage H, Tempst P, Reinberg D: Hu- 27. Yoshizawa T, Karim MF, Sato Y, Senokuchi anisms and emerging role in renal patho- man SirT1 interacts with histone H1 and T, Miyata K, Fukuda T, et al.: SIRT7 controls physiology. Kidney Int 83: 568–581, 2013 promotes formation of facultative het- hepatic lipid metabolism by regulating the 41. MorigiM,PericoL,RotaC,LongarettiL,Conti erochromatin. Mol Cell 16: 93–105, ubiquitin-proteasome pathway. Cell Metab S, Rottoli D, et al.: Sirtuin 3-dependent mito- 2004 19: 712–721, 2014 chondrial dynamic improvements protect 14. Zhu X, Liu Q, Wang M, Liang M, Yang X, Xu 28. North BJ, Marshall BL, Borra MT, Denu JM, against acute kidney injury. J Clin Invest 125: X, et al.: Activation of Sirt1 by resveratrol Verdin E: The human Sir2 ortholog, SIRT2, is 715–726, 2015 inhibits TNF-a induced inflammation in fi- an NAD1-dependent tubulin deacetylase. 42. Pérez MJ, Quintanilla RA: Development or broblasts. PLoS One 6: e27081, 2011 Mol Cell 11: 437–444, 2003 disease: Duality of the mitochondrial perme- 15. Langley E, Pearson M, Faretta M, Bauer U- 29. Dryden SC, Nahhas FA, Nowak JE, Goustin ability transition pore. Dev Biol 426: 1–7, 2017 M, Frye RA, Minucci S, et al.: Human SIR2 A-S, Tainsky MA: Role for human SIRT2 43. Chen Y, Zhang J, Lin Y, Lei Q, Guan K-L, deacetylates p53 and antagonizes PML/ NAD-dependent deacetylase activity in Zhao S, et al.: Tumour suppressor SIRT3 p53-induced cellular senescence. EMBO J control of mitotic exit in the cell cycle. Mol deacetylates and activates manganese su- 21: 2383–2396, 2002 Cell Biol 23: 3173–3185, 2003 peroxide dismutase to scavenge ROS. 16. Cheng H-L, Mostoslavsky R, Saito S, Manis JP, 30. North BJ, Rosenberg MA, Jeganathan KB, EMBO Rep 12: 534–541, 2011 Gu Y, Patel P, et al.: Developmental defects Hafner AV, Michan S, Dai J, et al.: SIRT2 44. Bause AS, Haigis MC: SIRT3 regulation of and p53 hyperacetylation in Sir2 homolog induces the checkpoint kinase BubR1 to mitochondrial oxidative stress. Exp Ger- (SIRT1)-deficient mice. Proc Natl Acad Sci U S increase lifespan. EMBO J 33: 1438–1453, ontol 48: 634–639, 2013 A 100: 10794–10799, 2003 2014 45. Schlicker C, Gertz M, Papatheodorou P, 17. Brunet A, Sweeney LB, Sturgill JF, Chua KF, 31. Nie H, Hong Y, Lu X, Zhang J, Chen H, Li Y, Kachholz B, Becker CFW, Steegborn C: Greer PL, Lin Y, et al.: Stress-dependent et al.: SIRT2 mediates oxidative stress-in- Substrates and regulation mechanisms for regulation of FOXO transcription factors by duced apoptosis of differentiated PC12 the human mitochondrial sirtuins Sirt3 and the SIRT1 deacetylase. Science 303: 2011– cells. Neuroreport 25: 838–842, 2014 Sirt5. JMolBiol382: 790–801, 2008 2015, 2004 32. Ramakrishnan G, Davaakhuu G, Kaplun L, 46. Xu Y, Liu L, Nakamura A, Someya S, 18. Dioum EM, Chen R, Alexander MS, Zhang Chung W-C, Rana A, Atfi A, et al.: Sirt2 de- Miyakawa T, Tanokura M: Studies on the Q, Hogg RT, Gerard RD, et al.: Regulation of acetylase is a novel AKT binding partner regulatory mechanism of isocitrate de- hypoxia-inducible factor 2alpha signaling critical for AKT activation by insulin. JBiol hydrogenase 2 using acetylation mimics. by the stress-responsive deacetylase sirtuin Chem 289: 6054–6066, 2014 Sci Rep 7: 9785, 2017 1. Science 324: 1289–1293, 2009 33. Krishnan J, Danzer C, Simka T, Ukropec J, 47. Hallows WC, Lee S, Denu JM: Sirtuins de- 19.PicardF,KurtevM,ChungN,Topark- Walter KM, Kumpf S, et al.: Dietary obesity- acetylate and activate mammalian acetyl- Ngarm A, Senawong T, Machado De associated Hif1a activation in adipocytes CoA synthetases. Proc Natl Acad Sci U S A Oliveira R, et al.: Sirt1 promotes fat restricts fatty acid oxidation and energy ex- 103: 10230–10235, 2006 mobilization in white adipocytes by re- penditure via suppression of the Sirt2-NAD1 48. Haigis MC, Mostoslavsky R, Haigis KM, pressing PPAR-gamma. Nature 429: 771– system. Genes Dev 26: 259–270, 2012 Fahie K, Christodoulou DC, Murphy AJ, 776, 2004 34. Jing E, Gesta S, Kahn CR: SIRT2 regulates et al.: SIRT4 inhibits glutamate de- 20. Frescas D, Valenti L, Accili D: Nuclear trap- adipocyte differentiation through FoxO1 hydrogenase and opposes the effects of ping of the forkhead transcription factor acetylation/deacetylation. Cell Metab 6: calorie restriction in pancreatic beta cells. FoxO1 via Sirt-dependent deacetylation 105–114, 2007 Cell 126: 941–954, 2006 promotes expression of glucogenetic genes. 35. Lombard DB, Alt FW, Cheng H-L, 49. Hirschey MD, Shimazu T, Goetzman E, Jing JBiolChem280: 20589–20595, 2005 Bunkenborg J, Streeper RS, Mostoslavsky R, E, Schwer B, Lombard DB, et al.: SIRT3 21. Rodgers JT, Lerin C, Haas W, Gygi SP, et al.: Mammalian Sir2 homolog SIRT3 reg- regulates mitochondrial fatty-acid oxida- Spiegelman BM, Puigserver P: Nutrient ulates global mitochondrial lysine acetyla- tion by reversible enzyme deacetylation. control of glucose homeostasis through a tion. Mol Cell Biol 27: 8807–8814, 2007 Nature 464: 121–125, 2010 complex of PGC-1alpha and SIRT1. Nature 36. Ahn B-H, Kim H-S, Song S, Lee IH, Liu J, 50. Shimazu T, Hirschey MD, Hua L, Dittenhafer- 434: 113–118, 2005 Vassilopoulos A, et al.: A role for the Reed KE, Schwer B, Lombard DB, et al.:

J Am Soc Nephrol 29: ccc–ccc, 2018 Role of Sirtuins in the Kidney 9 REVIEW www.jasn.org

SIRT3 deacetylates mitochondrial 3-hydroxy- angiotensin system via SIRT1 modulation in 79. Tran MT, Zsengeller ZK, Berg AH, Khankin 3-methylglutaryl CoA synthase 2 and regu- podocytes. Exp Mol Pathol 102: 97–105, 2017 EV, Bhasin MK, Kim W, et al.: PGC1a drives lates ketone body production. Cell Metab 64. Mattagajasingh I, Kim C-S, Naqvi A, Yamamori NAD biosynthesis linking oxidative metab- 12: 654–661, 2010 T, Hoffman TA, Jung S-B, et al.: SIRT1 pro- olism to renal protection. Nature 531: 528– 51. Laurent G, German NJ, Saha AK, de Boer motes endothelium-dependent vascular re- 532, 2016 VCJ, Davies M, Koves TR, et al.: SIRT4 co- laxation by activating endothelial nitric oxide 80. Funk JA, Schnellmann RG: Accelerated re- ordinates the balance between lipid syn- synthase. Proc Natl Acad Sci U S A 104: covery of renal mitochondrial and tubule thesis and catabolism by repressing malonyl 14855–14860, 2007 homeostasis with SIRT1/PGC-1a activation CoA decarboxylase. Mol Cell 50: 686–698, 65. Benigni A, Perico L, Macconi D: Mitochon- following ischemia-reperfusion injury. Tox- 2013 drial dynamics is linked to longevity and icol Appl Pharmacol 273: 345–354, 2013 52. Jeong SM, Xiao C, Finley LWS, Lahusen T, protects from end-organ injury: The emerg- 81. Ortega-Domínguez B, Aparicio-Trejo OE, Souza AL, Pierce K, et al.: SIRT4 has tumor- ing role of sirtuin 3. Antioxid Redox Signal García-Arroyo FE, León-Contreras JC, suppressive activity and regulates the cel- 25: 185–199, 2016 Tapia E, Molina-Jijón E, et al.: Curcumin lular metabolic response to DNA damage 66. Perico L, Morigi M, Benigni A: Mitochon- prevents cisplatin-induced renal alterations by inhibiting mitochondrial glutamine me- drial sirtuin 3 and renal diseases. Nephron in mitochondrial bioenergetics and dy- tabolism. Cancer Cell 23: 450–463, 2013 134: 14–19, 2016 namic. Food Chem Toxicol 107[Pt A]: 373– 53. Anderson KA, Huynh FK, Fisher-Wellman K, 67. Perico L, Morigi M, Rota C, Breno M, Mele 385, 2017 Stuart JD, Peterson BS, Douros JD, et al.: C, Noris M, et al.: Human mesenchymal 82. Li N, Xie H, Li L, Wang J, Fang M, Yang N, SIRT4 Is a lysine deacylase that controls stromal cells transplanted into mice stimu- et al.: Effects of honokiol on sepsis-induced leucine metabolism and insulin secretion. late renal tubular cells and enhance mito- acute kidney injury in an experimental Cell Metab 25: 838–855.e15, 2017 chondrial function. Nat Commun 8: 983, model of sepsis in rats. Inflammation 37: 54. Nakagawa T, Lomb DJ, Haigis MC, 2017 1191–1199, 2014 Guarente L: SIRT5 deacetylates carbamoyl 68. Huang W, Liu H, Zhu S, Woodson M, Liu R, 83. Li Y, Ye Z, Lai W, Rao J, Huang W, Zhang X, phosphate synthetase 1 and regulates the TiltonRG,etal.:Sirt6deficiency results in et al.: Activation of sirtuin 3 by silybin at- urea cycle. Cell 137: 560–570, 2009 progression of glomerular injury in the kid- tenuates mitochondrial dysfunction in cis- 55. Rardin MJ, He W, Nishida Y, Newman JC, ney. Aging (Albany NY) 9: 1069–1083, 2017 platin-induced acute kidney injury. Front Carrico C, Danielson SR, et al.: SIRT5 regu- 69. Mercado A, Melo Z, Tovar A, Rajaram R, Pharmacol 8: 178, 2017 lates the mitochondrial lysine succinylome Cruz-Rangel S, Ryu D, et al.: The K1:Cl- 84. Xu S, Gao Y, Zhang Q, Wei S, Chen Z, Dai X, and metabolic networks. Cell Metab 18: cotransporter KCC4 is activated by deace- et al.: SIRT1/3 activation by resveratrol at- 920–933, 2013 tylation induced by the sirtuin7 (SIRT7). tenuates acute kidney injury in a septic rat 56. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, FASEB J 29 [Suppl 1], 2015 model. Oxid Med Cell Longev 2016: et al.: Sirt5 is a NAD-dependent protein ly- 70. Hao C-M, Haase VH: Sirtuins and their rel- 7296092, 2016 sine demalonylase and desuccinylase. Sci- evance to the kidney. JAmSocNephrol21: 85. Pan JS-C, Huang L, Belousova T, Lu L, Yang Y, ence 334: 806–809, 2011 1620–1627, 2010 Reddel R, et al.: Stanniocalcin-1 inhibits renal 57. Nishida Y, Rardin MJ, Carrico C, He W, Sahu 71. Thadhani R, Pascual M, Bonventre JV: Acute ischemia/reperfusion injury via an AMP-acti- AK, Gut P, et al.: SIRT5 regulates both cy- renal failure. NEnglJMed334: 1448–1460, vated protein kinase-dependent pathway. J tosolic and mitochondrial protein malony- 1996 Am Soc Nephrol 26: 364–378, 2015 lation with glycolysis as a major target. Mol 72. Lewington AJP, Cerdá J, Mehta RL: Raising 86. Remuzzi G, Schieppati A, Ruggenenti P: Cell 59: 321–332, 2015 awareness of acute kidney injury: A global Clinical practice. Nephropathy in patients 58. Wang Z, Ying Z, Bosy-Westphal A, Zhang J, perspective of a silent killer. Kidney Int 84: with type 2 diabetes. NEnglJMed346: Schautz B, Later W, et al.: Specificmetabolic 457–467, 2013 1145–1151, 2002 rates of major organs and tissues across 73. Bonventre JV, Yang L: Cellular pathophysi- 87. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, adulthood: Evaluation by mechanistic ology of ischemic acute kidney injury. JClin de Boer IH, Goldstein-Fuchs J, et al.: Di- model of resting energy expenditure. Am J Invest 121: 4210–4221, 2011 abetic kidney disease: A report from an Clin Nutr 92: 1369–1377, 2010 74.BrooksC,WeiQ,ChoS-G,DongZ:Regu- ADA consensus conference. Am J Kidney 59. Bhargava P, Schnellmann RG: Mitochon- lation of mitochondrial dynamics in acute Dis 64: 510–533, 2014 drial energetics in the kidney. Nat Rev kidney injury in cell culture and rodent 88.KitadaM,KumeS,Takeda-WatanabeA, Nephrol 13: 629–646, 2017 models. JClinInvest119: 1275–1285, Kanasaki K, Koya D: Sirtuins and renal diseases: 60. Perico L, Conti S, Benigni A, Remuzzi G: 2009 Relationship with aging and diabetic ne- Podocyte-actin dynamics in health and dis- 75. Dong YJ, Liu N, Xiao Z, Sun T, Wu SH, Sun phropathy. Clin Sci (Lond) 124: 153–164, 2013 ease. Nat Rev Nephrol 12: 692–710, 2016 WX, et al.: Renal protective effect of sirtuin 89. Baur JA, Pearson KJ, Price NL, Jamieson 61. Zhang D, Li S, Cruz P, Kone BC: Sirtuin 1 1. JDiabetesRes2014: 843786, 2014 HA, Lerin C, Kalra A, et al.: Resveratrol im- functionally and physically interacts with 76. Guan Y, Hao C-M: SIRT1 and kidney func- proves health and survival of mice on a high- disruptor of telomeric silencing-1 to regu- tion. Kidney Dis (Basel) 1: 258–265, 2016 calorie diet. Nature 444: 337–342, 2006 late alpha-ENaC transcription in collecting 77. Hasegawa K, Wakino S, Yoshioka K, 90. Lagouge M, Argmann C, Gerhart-Hines Z, duct. JBiolChem284: 20917–20926, 2009 Tatematsu S, Hara Y, Minakuchi H, et al.: Meziane H, Lerin C, Daussin F, et al.: Re- 62. Miyazaki R, Ichiki T, Hashimoto T, Inanaga Kidney-specific overexpression of Sirt1 sveratrol improves mitochondrial function K, Imayama I, Sadoshima J, et al.: SIRT1, a protects against acute kidney injury by re- and protects against metabolic disease by longevity gene, downregulates angiotensin taining peroxisome function. JBiolChem activating SIRT1 and PGC-1alpha. Cell 127: II type 1 receptor expression in vascular 285: 13045–13056, 2010 1109–1122, 2006 smooth muscle cells. Arterioscler Thromb 78. Fan H, Yang H-C, You L, Wang Y-Y, He W-J, 91. Pfl uger PT, Herranz D, Velasco-Miguel S, Vasc Biol 28: 1263–1269, 2008 Hao C-M: The histone deacetylase, SIRT1, Serrano M, Tschöp MH: Sirt1 protects 63. Chandel N, Ayasolla K, Wen H, Lan X, contributes to the resistance of young mice against high-fat diet-induced metabolic Haque S, Saleem MA, et al.: Vitamin D re- to ischemia/reperfusion-induced acute damage. Proc Natl Acad Sci U S A 105: ceptor deficit induces activation of renin kidney injury. Kidney Int 83: 404–413, 2013 9793–9798, 2008

10 Journal of the American Society of Nephrology J Am Soc Nephrol 29: ccc–ccc,2018 www.jasn.org REVIEW

1 92. Liu R, Zhong Y, Li X, Chen H, Jim B, Zhou M- through inhibition of ER stress via up-reg- mononucleotide, an NAD precursor, res- M, et al.: Role of transcription factor acety- ulation of SIRT1, followed by induction of cues age-associated susceptibility to AKI lation in diabetic kidney disease. Diabetes HO-1 and thioredoxin. Int J Mol Sci 18: in a sirtuin 1-dependent manner. JAmSoc 63: 2440–2453, 2014 305, 2017 Nephrol 28: 2337–2352, 2017 93. Chuang PY, Dai Y, Liu R, He H, Kretzler M, 105. Li J, Qu X, Ricardo SD, Bertram JF, Nikolic- 116. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Jim B, et al.: Alteration of forkhead box O Paterson DJ: Resveratrol inhibits renal fi- Isshiki K, Araki S, et al.: Calorie restriction (foxo4) acetylation mediates apoptosis of brosis in the obstructed kidney: Potential enhances cell adaptation to hypoxia podocytes in diabetes mellitus. PLoS One 6: role in deacetylation of Smad3. Am J Pathol through Sirt1-dependent mitochondrial e23566, 2011 177: 1065–1071, 2010 autophagy in mouse aged kidney. JClin 94. Hasegawa K, Wakino S, Simic P, Sakamaki Y, 106. Zhang Y, Connelly KA, Thai K, Wu X, Kapus Invest 120: 1043–1055, 2010 Minakuchi H, Fujimura K, et al.: Renal tu- A, Kepecs D, et al.: Sirtuin 1 activation re- 117. Chuang PY, Cai W, Li X, Fang L, Xu J, bular Sirt1 attenuates diabetic albuminuria duces transforming growth factor-b1-in- Yacoub R, et al.: Reduction in podocyte by epigenetically suppressing Claudin-1 duced fibrogenesis and affords organ SIRT1 accelerates kidney injury in aging overexpression in podocytes. Nat Med 19: protection in a model of progressive, ex- mice. Am J Physiol Renal Physiol 313: 1496–1504, 2013 perimental kidney and associated cardiac F621–F628, 2017 95. Zhao Y, Wei J, Hou X, Liu H, Guo F, Zhou Y, disease. Am J Pathol 187: 80–90, 2017 118. Kwon Y, Kim J, Lee C-Y, Kim H: Expression et al.: SIRT1 rs10823108 and FOXO1 107. Simic P, Williams EO, Bell EL, Gong JJ, of SIRT1 and SIRT3 varies according to age rs17446614 responsible for genetic sus- Bonkowski M, Guarente L: SIRT1 sup- in mice. Anat Cell Biol 48: 54–61, 2015 ceptibility to diabetic nephropathy. Sci Rep presses the epithelial-to-mesenchymal 119. Benigni A, Corna D, Zoja C, Sonzogni A, 7: 10285, 2017 transition in cancer metastasis and organ Latini R, Salio M, et al.: Disruption of the 96. Maeda S, Koya D, Araki SI, Babazono T, fibrosis. Cell Rep 3: 1175–1186, 2013 Ang II type 1 receptor promotes longevity Umezono T, Toyoda M, et al.: Association 108. Kida Y, Zullo JA, Goligorsky MS: Endothe- in mice. JClinInvest119: 524–530, 2009 between single nucleotide polymorphisms lial sirtuin 1 inactivation enhances capillary 120. Zhang N, Li Z, Mu W, Li L, Liang Y, Lu M, within genes encoding sirtuin families and rarefaction and fibrosis following kidney et al.: Calorie restriction-induced SIRT6 ac- diabetic nephropathy in Japanese subjects injury through Notch activation. Biochem tivation delays aging by suppressing NF-kB with type 2 diabetes. Clin Exp Nephrol 15: Biophys Res Commun 478: 1074–1079, signaling. Cell Cycle 15: 1009–1018, 2016 381–390, 2011 2016 121. Ning Y-C, Cai G-Y, Zhuo L, Gao J-J, Dong D, 97. Zhang B, Cui S, Bai X, Zhuo L, Sun X, Hong 109. Vasko R, Xavier S, Chen J, Lin CHS, Ratliff B, Cui S-Y, et al.: Beneficial effects of short- Q, et al.: SIRT3 overexpression antagonizes Rabadi M, et al.: Endothelial sirtuin 1 de- term calorie restriction against cisplatin- high glucose accelerated cellular senes- ficiency perpetrates nephrosclerosis induced acute renal injury in aged rats. cence in human diploid fibroblasts via the through downregulation of matrix metal- Nephron, Exp Nephrol 124: 19–27, 2013 SIRT3-FOXO1 signaling pathway. Age loproteinase-14: Relevance to fibrosis of 122. Mitchell SJ, Martin-Montalvo A, Mercken (Dordr) 35: 2237–2253, 2013 vascular senescence. JAmSocNephrol25: EM, Palacios HH, Ward TM, Abulwerdi G, 98. Gounden S, Phulukdaree A, Moodley D, 276–291, 2014 et al.: The SIRT1 activator SRT1720 extends Chuturgoon A: Increased SIRT3 expression 110. Han SH, Wu MY, Nam BY, Park JT, Yoo TH, lifespan and improves health of mice fed a and antioxidant defense under hypergly- Kang SW, et al.: PGC-1a protects from standard diet. Cell Rep 6: 836–843, 2014 cemic conditions in HepG2 cells. Metab notch-induced kidney fibrosis develop- 123. Sinclair DA, Guarente L: Small-molecule Syndr Relat Disord 13: 255–263, 2015 ment. JAmSocNephrol28: 3312–3322, allosteric activators of sirtuins. Annu Rev 99. Wang XX, Edelstein MH, Gafter U, Qiu L, 2017 Pharmacol Toxicol 54: 363–380, 2014 Luo Y, Dobrinskikh E, et al.: G protein-coupled 111. Sundaresan NR, Gupta M, Kim G, 124. Farghali H, Kutinová Canová N, LekicN: bile acid receptor TGR5 activation inhibits kid- Rajamohan SB, Isbatan A, Gupta MP: Sirt3 Resveratrol and related compounds as an- ney disease in obesity and diabetes. JAmSoc blocks the cardiac hypertrophic response tioxidants with an allosteric mechanism of Nephrol 27: 1362–1378, 2016 by augmenting Foxo3a-dependent antiox- action in epigenetic drug targets. Physiol 100.YiW,XieX,DuM,BuY,WuN,YangH, idant defense mechanisms in mice. JClin Res 62: 1–13, 2013 et al.: Green tea polyphenols ameliorate the Invest 119: 2758–2771, 2009 125. Dang W: The controversial world of sirtuins. early renal damage induced by a high-fat 112. Sundaresan NR, Bindu S, Pillai VB, Samant Drug Discov Today Technol 12: e9–e17, diet via ketogenesis/SIRT3 pathway. Oxid S, Pan Y, Huang J-Y, et al.: SIRT3 blocks 2014 Med Cell Longev 2017: 9032792, 2017 aging-associated tissue fibrosis in mice by 126. Bonkowski MS, Sinclair DA: Slowing ageing 1 101. Liu Y: Cellular and molecular mechanisms of deacetylating and activating glycogen by design: The rise of NAD and sirtuin-ac- renal fibrosis. Nat Rev Nephrol 7: 684–696, synthase kinase 3b. Mol Cell Biol 36: 678– tivating compounds. Nat Rev Mol Cell Biol 2011 692, 2015 17: 679–690, 2016 102. He W, Wang Y, Zhang M-Z, You L, Davis LS, 113. Li N, Zhang J, Yan X, Zhang C, Liu H, Shan X, 127. Pillai VB, Samant S, Sundaresan NR, Fan H, et al.: Sirt1 activation protects the et al.: SIRT3-KLF15 signaling ameliorates Raghuraman H, Kim G, Bonner MY, et al.: mouse renal medulla from oxidative injury. kidney injury induced by hypertension. Honokiol blocks and reverses cardiac hy- JClinInvest120: 1056–1068, 2010 Oncotarget 8: 39592–39604, 2017 pertrophy in mice by activating mitochon- 103. Chang JW, Kim H, Baek CH, Lee RB, Yang 114. Braidy N, Guillemin GJ, Mansour H, Chan- drial Sirt3. Nat Commun 6: 6656, 2015 WS, Lee SK: Up-regulation of SIRT1 reduces Ling T, Poljak A, Grant R: Age related 128. Camacho-Pereira J, Tarragó MG, Chini endoplasmic reticulum stress and renal fi- changes in NAD1 metabolism oxidative CCS, Nin V, Escande C, Warner GM, et al.: brosis. Nephron 133: 116–128, 2016 stress and Sirt1 activity in wistar rats. PLoS CD38 dictates age-related NAD decline 104. Kim H, Baek CH, Lee RB, Chang JW, Yang One 6: e19194, 2011 and mitochondrial dysfunction through an WS, Lee SK: Anti-fibrotic effect of losartan, 115. Guan Y, Wang S-R, Huang X-Z, Xie Q-H, SIRT3-dependent mechanism. Cell Metab an angiotensin II receptor blocker, is mediated Xu Y-Y, Shang D, et al.: Nicotinamide 23: 1127–1139, 2016

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