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Sirtuins in Renal Health and Disease

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Sirtuins in Renal Health and Disease 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,
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