Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

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A Land of Controversy: Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

Jing-Fu Bao ,1 Pan-Pan Hu,1 Qin-Ying She ,2 and Aiqing Li1

1State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China 2National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China

ABSTRACT Cardiac hypertrophy is a common feature in patients with CKD. Recent studies amino-terminal and approximately revealed that two phosphate regulators, fibroblast growth factor-23 and 12 kDa carboxy-terminal (cFGF-23) a-Klotho, are highly involved in the pathophysiologic process of CKD-induced car- fragments, and the latter can compete diac hypertrophy. With decreasing renal function, elevated fibroblast growth factor- with iFGF-23 for binding to the FGF re- 23 and decreased a-Klotho may contribute to cardiac hypertrophy by targeting the ceptor (FGFR), thus exerting certain bi- heart directly or by inducing systemic changes, such as vascular injury, hemody- ologic functions (Figure 1).6,7 Unlike namic disorders, and inflammation. However, several studies have demonstrated other FGF subfamilies, the FGF-19 sub- that disturbances in the fibroblast growth factor-23/a-Klotho axis do not lead to family lacks a heparin binding domain, cardiac hypertrophy. In this review, we describe the cardiac effects of the fibroblast which is replaced by a Klotho binding growth factor-23/a-Klotho axis and summarize recent progress in this field. In ad- domain. Hence, low affinity to heparin dition, we present not only the main controversies in this field but also provide sulfate enables FGF-19 subfamily mem- possible directions to resolve these disputes. bers to enter the bloodstream and function as endocrine factors.8–10 On the JASN 31: 1423–1434, 2020. doi: https://doi.org/10.1681/ASN.2020010081 other hand, the lack of a heparin binding domain renders these proteins incapable of forming the FGF-FGFR-heparin sul- Cardiovascular complications of CKD FGF-23/a-Klotho axis is unable to in- fate complex and activating downstream seriously affect the prognosis of patients duce cardiac hypertrophy. This review signaling.11 Klotho, a single-pass trans- with CKD.1 Cardiac hypertrophy is the will focus on the FGF-23/a-Klotho axis membrane protein, interacts with FGF- most common of such complications in uremic cardiac hypertrophy, present 19 subfamily members and FGFR to and underlies the pathology for other controversies about their roles in cardio- form the FGF-FGFR-Klotho complex, heart conditions. However, there are still vascular abnormalities, and provide di- and then activates FGFR signaling.12,13 many unknowns regarding the patho- rection for future research. physiology of CKD-induced cardiac hy- a-Klotho pertrophy.2 To date, several factors are Klotho is a membrane protein that demonstrates antiaging effects.14 It can be di- considered to be involved in the patho- BRIEF INTRODUCTION TO THE genesis of uremic cardiac hypertrophy, vided into three subtypes: a-Klotho, FGF-23/a-KLOTHO AXIS 15–17 including hemodynamic overload, sys- b-Klotho, and g-Klotho. Among fl temic in ammation, accumulation of FGF-23 3 uremic toxins, and other factors. Recent FGF-23, a newly discovered FGF-19 sub- fi Published online ahead of print. Publication date ndings suggest that two proteins that are family member, is an approximately available at www.jasn.org. highly involved in phosphate metabolism, 32 kDa glycoprotein that is mainly fi Correspondence: Dr. Aiqing Li, State Key Labora- broblast growth factor-23 (FGF-23) and secreted by osteocytes or osteoblasts.4 tory of Organ Failure Research, National Clinical its coreceptor a-Klotho play pivotal roles After removal of the signal peptide and Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, 1838 North in cardiovascular abnormalities (espe- glycosylation, intact FGF-23 (iFGF-23) Guangzhou Avenue, Guangzhou 510515, China. cially cardiac hypertrophy) in the setting is secreted into the blood (Figure 1).5 Email: [email protected] 176 179 of CKD. However, some researchers dis- iFGF-23 can be cleaved at R XXR / Copyright © 2020 by the American Society of 180 pute this, arguing that disturbance in the S into inactive approximately 18 kDa Nephrology

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roidism lead to increased circulating levels of FGF-23. Often, worse kidney function is associated with higher circulating FGF-23 concentrations.27–29 Al- though the increase in FGF-23 helps maintain a normal serum phosphate level, epidemiologic studies revealed that a high circulating level of FGF-23 is an independent risk factor for cardiovascular disease and may increase mortality in patients with CKD.30–35

Uremic Cardiac Hypertrophy and FGF-23 The primary link between FGF-23 and cardiovascular complications in CKD is left ventricular hypertrophy (LVH).33,36 The detailed mechanism of FGF-23– induced LVH was first revealed by Faul et al.33 A series of studies confirmed that hypertrophic growth of cardiomyocytes Figure 1. The maturation and disintegration of FGF-23. FGF-23 precursor contains 251 can be induced by FGF-23, and that this amino acids (aa) and can be divided into a signal sequence (24 aa), a FGFR binding domain effect does not require FGFR-1/Klotho (155 aa), and an a-Klotho binding domain (72 aa). After removal of the signal sequence, iFGF-23 is secreted into the blood or cleaved between aa 179 and 180 into inactive amino- but does need the presence of FGFR- 26,33,37 fi terminal FGF-23 and active cFGF-23. 4. Speci cally, FGF-23 binds to FGFR-4 in cardiomyocytes and results in stimulation of the phospholipase Cg these, a-Klotho and b-Klotho interact and inhibits the activation of 1,25-dihy- (PLCg)/calcineurin pathway,37 which 23 with FGF-23 and FGF-19/FGF-21, re- droxyvitamin D3. In the parathyroid is an important mediator of cardiac hy- spectively, and assist the binding of gland, FGF-23 restricts the synthesis of pertrophy in response to a majority of FGF and FGFR.15,17,18 However, the bi- parathyroid hormone.24 In the heart, pathologic stimuli (including CKD con- ologic function of the third member, Klotho is expressed in the sinoatrial ditions).38,39 FGFR-4 null mice fed a g-Klotho, remains unclear. In mam- node, but the mRNA level of Klotho is high-phosphate diet37 and 5/6 nephrec- mals, a-Klotho (abbreviated as Klotho fairly low or even undetectable in the tomized rats treated with an FGFR-4 an- below) is considered to exist in two myocardium.25 Studies using either tagonist37 or a calcineurin inhibitor40 all forms in vivo: membranous Klotho PCR or RNA sequencing confirmed low demonstrated no obvious cardiac hyper- (mKlotho) and secreted Klotho (sKlotho). levels or even a lack of Klotho mRNA in trophy. These findings further indicate The secreted enzymes A disintegrin and mouse and human heart,22 whereas Klo- an important role of FGFR-4/PLCg/cal- metalloproteinase-10 (ADAM-10), tho protein can be detected by Western cineurin signaling in FGF-23–induced ADAM-17, and b-site amyloid precur- blotting.26 Such results may indicate that cardiac hypertrophy. Our studies also re- sor protein cleaving enzyme-1 can incise the actions of FGF-23 and Klotho in car- vealed that microRNA-30, which is an en- the extracellular domain of mKlotho, diac tissue are different from those in the dogenous post-transcriptional inhibitor of which then generates sKlotho.19,20 Al- kidney and parathyroid gland. calcineurin,41 attenuates CKD-induced ternative splicing of Klotho mRNA gen- LVH (unpublished data). In addition, ex- erates sKlotho as well.21 ogenous microRNA-30 supplementation FGF-23 exerts its functions mainly CARDIAC EFFECTS OF FGF-23 IN also inhibits FGF-23–induced cardio- through FGFR-1; however, FGF-23 CKD myocyte hypertrophy (unpublished needs the assistance of mKlotho to ac- data). Recently, Han et al.42 found tivate FGFR-1.12 The expression of CKD is a common result of various kid- that mice with cardiomyocyte FGFR-4 mKlotho is tissue specific, predomi- ney and urologic diseases, with a gradual deletion exhibit resistance to FGF-23– nantly in distal convoluted tubules of decrease in the number of functional induced cardiac hypertrophy, which pro- the kidney and chief cells in the parathy- nephrons and excretory function. As vides further evidence for the vital role of roid gland.22 In the kidney, FGF-23 sup- a result of impaired excretory capacity, cardiac FGFR-4 in FGF-23–induced car- presses the reabsorption of phosphate hyperphosphatemia and hyperparathy- diac hypertrophy.

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The myocardium of patients with can be normalized by a high-phosphate contribute to cardiac hypertrophy.22,33 CKD26 and CKD rats43 can secrete diet. Leifheit-Nestler et al.26 revealed the FGF-23 and exert a paracrine effect, sug- Remarkably, there are few studies that presence of Klotho protein in cardiac gesting there may be a local regulatory seem to refute or support the prohyper- muscle, which suggests that the heart system of FGF-23. Leifheit-Nestler trophic effect of FGF-23. Shalhoub can take up sKlotho from the circula- et al.26 confirmed that FGF-23 promotes et al.52 found that administration of tion. A series of studies found that cardiac hypertrophy from multiple per- FGF-23–neutralizing antibody in CKD sKlotho inhibits the prohypertrophic spectives and, in a follow-up study, rats did not attenuate cardiac hypertro- signaling pathway and exerts unique Leifheit-Nestler et al.43 further revealed phy. On the other hand, ferric citrate ad- biologic functions that are indepen- that myocardial FGF-23 significantly ministration from 6 to 10 weeks of age dent of FGF-23.64–67 For example, promotes LVH in patients with CKD in reduces iFGF-23 and significantly im- sKlotho directly binds to the type II a paracrine manner. In addition, FGF-23 proves cardiac function in Col4a3 TGF-b receptor,68 blocking TGF-b1 released by cardiomyocytes also stimu- knockout mice (a model of progressive signaling, and TGF-b169 is highly in- lates fibroblasts to secrete TGF-b, con- CKD).53 These two seemingly contradic- volved in cardiac hypertrophy. nective tissue growth factor, and other tory results may be due to interference of Intriguingly, sKlotho suppresses car- profibrotic factors.44 These studies indi- other factors related to cardiac hypertro- diac hypertrophy that is induced by Ang- cate that the paracrine role of FGF-23 in phy. For example, FGF-23 neutralization II,58 TGF-b,58,67 or isoprenaline58,67,70; cardiac tissue may not be ignored in facilitates aortic calcification and severe thus, sKlotho demonstrates a broad CKD-induced cardiac hypertrophy. hyperphosphatemia,52 which are prohy- spectrum antihypertrophic effects. sKlo- pertrophic stimuli. In addition, it is pos- tho inhibits the production of reactive Controversies sible that ferric citrate improves cardiac oxygen species (ROS), and sKlotho de- Although a number of studies33,36 indi- function by alleviating iron deficiency ficiency may lead to an increase in ROS cate that FGF-23 increases the incidence and anemia rather than by lowering in myocardial tissue and induce cardiac of cardiovascular abnormalities, there FGF-23.53 Therefore, these two studies hypertrophy.71 In addition, several sig- also are studies that do not seem to sup- were unable to prove or exclude the di- naling pathways that may be involved port this conclusion. X-linked hypo- rect cardiac role of FGF-23. in CKD-induced cardiac injury, includ- phosphatemia (XLH), which causes an ing the PI3K,65 WNT,72,73 and NF-kB increased concentration of FGF-23, can pathways,74 can be regulated by sKlotho. be used as a convenient model to inves- CARDIAC EFFECTS OF KLOTHO IN Recently, a specific receptor for sKlotho, tigate the role of FGF-23 in the myocar- CKD monosialoganglioside, was identified; dium. Recently, Pastor-Arroyo et al.45 sKlotho binds to it and inhibits raft- found that the XLH mouse model, The kidney’s distal tubules are a main dependent PI3K signaling.75 This illus- which has normal kidney function, ex- source of Klotho and sKlotho.22 In the trates that sKlotho can inhibit the hibits high circulating FGF-23 and hy- setting of CKD, deficiency in Klotho and translocation of transient receptor po- pophosphatemia and has no activation sKlotho can be caused by a reduction in tential cation channel, subfamily C, of the calcineurin pathway in the myo- functional nephrons and inhibition of member 6 (TRPC6), an ion channel cardium; they also did not observe LVH Klotho expression. CKD-related factors that is involved in the formation of car- or abnormal cardiac function in these such as angiotensin II (Ang-II),54,55 in- diac hypertrophy.65,76,77 mice. Although this result is consistent flammatory cytokines,56,57 phosphate,58 with the results from some groups,46,47 deficiencies in vitamin D59 and erythro- Controversies other studies have observed significant poietin,60,61 or even FGF-2362 can trig- Although animal studies have estab- cardiac hypertrophy in patients with ger the suppression of Klotho. lished a clear relationship between XLH or XLH models.48–50 The reasons Klotho and the cardiovascular system, for these differences may depend on fac- Uremic Cardiac Hypertrophy and some clinical studies have failed to detect tors other than FGF-23, including age, Klotho an independent association between diet, and genetic background (Table 1). Animal experiments established a clear sKlotho level and left ventricular mass In addition, XLH and CKD exert different relationship between Klotho and the index in patients on hemodialysis.78–80 physiologic effects, such as hypophospha- cardiovascular system. Klotho-null mice In patients with CKD from stage 1 to 5 temia in XLH versus hyperphosphatemia develop CKD-like cardiovascular phe- (predialysis), however, sKlotho demon- in CKD, and these factors may signifi- notypes, such as vascular calcification, strates a significant inverse association cantly affect the myocardial effects of cardiac hypertrophy, and fibrosis.14,33,58,63 with left ventricular mass index.81 An- FGF-23 (Figure 2). For example, Liu However, Klotho mRNA is not de- other parameter of cardiac hypertrophy, et al.51 showed that overexpression of tected in the myocardium, aside from the wall thickness of the left ventricle, FGF-23 leads to hypotension and cardiac the sinoatrial node25; thus, loss of Klotho has an inverse association with sKlotho hypertrophy, and that these abnormalities in the myocardium may not directly in patients on dialysis, whereas such an

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Table 1. The comparison of the different high circulating FGF-23 models Model (genetic background) Circulating FGF-23 (model:control)a Blood-Related Parameters Cardiac Changes Reference 80 mg/kg per d FGF-23 IOCV for 5 d (c 1 i) FGF-23 ↑ (3.2:1) / LVH 33 (C57BL/6J) Klotho heterozygous (/) (c 1 i) FGF-23 ↑ (3.0:1) Phosphate ↑ LVH 33

Active VitD3 ↑ 5/6 nephrectomy (Sprague Dawley) (c 1 i) FGF-23 ↑ (12.5:1) Creatinine ↑ LVH 33

CCreatinine ↓ BUN ↑ Systolic pressure ↑ 5/6 nephrectomy (Sprague Dawley) (c 1 i) FGF-23 ↑ (3.5:1) Creatinine ↑ LVH 37

CCreatinine ↓ BUN ↑ Systolic pressure ↑ Diastolic pressure ↑ Phosphate → 2.0% phosphate diet for 12 wk (C57BL/6) (c 1 i) FGF-23 ↑ (6.0:1) BUN → LVH 37 75 mg/kg per d FGF-23 IP for 5 d (C57BL/6) FGF-23 ↑ (/) Systolic pressure ↑ LVH 42 2.0% phosphate diet for 3 mo (C57BL/6) iFGF-23 ↑ (5.6:1) / LVH 121 121 5/6 nephrectomy (Sprague Dawley) iFGF-23 ↑ (/) CCreatinine ↓ LVH BUN ↑ Systolic pressure ↑ Diastolic pressure ↑ Phosphate ↑ PhexC733R (C3Heb/FeJ) iFGF-23 ↑ (12.8:1) Phosphate ↓ No changes 45 Calcium → sKlotho ↓

Active VitD3 ↓ PTH ↑ BUN → Creatinine → Systolic pressure ↓ Cholesterol → Hyp (C57BL/6J) / Systolic pressure → Smaller heart 47 Hyp (C57BL/6) iFGF-23 ↑ (14.4:1) Aldosterone ↓ LVH 50 Transgenic human FGF-23 in liver / Systolic pressure ↓ LVH 51 (C57BL/6J) Phosphate ↓ Epinephrine ↑ Norepinephrine ↑ Dopamine ↑ Ang-II ↑ Cortisol ↑ Glucose ↓

IOCV, injection of caudal vein; (c 1 i) FGF-23, C-terminal and intact FGF-23; /, not mentioned; VitD3, vitamin D3;CCreatinine, creatinine clearance; →,nosigniﬁcant difference between model group and control group; IP, intraperitoneal injection; PTH, parathyroid hormone; Hyp, X-linked semidominant mutation of Phex gene that causes hypophosphatemia and high circulating FGF-23, whereas does not affect kidney functions. aModel:control is calculated by average value of each group.

associationdoesnotexistinpredialysis changes in the heart or predict cardiovas- the principal reason for these unexpected patients.79,80 As mentioned by Zhang cular risk in patients with heart disease results.84 Indeed, a high concentration of et al.,80 such discrepancies may be who have normal renal function.82 bilirubin (250 mg/L) can significantly re- caused by dialysis, which is associated Surprisingly,astudybySugiura duce the measured value of sKlotho.84 In with such factors as interdialytic weight et al.83 found increased sKlotho levels addition, different kits contain different gain, ultrafiltration, dialysate, and dia- in patients with CKD. Authors of a sub- sKlotho antibodies, which are directed to lyzers that do not apply to nondialysis pa- sequent study that found a significant different epitopes, and such differences tients with CKD. Furthermore, sKlotho increase in sKlotho level in CKD hypoth- may obviously influence the measure- also does not associate with pathologic esized that the reliability of assay kits is ments. Currently, the best way to measure

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to uremic cardiac hypertrophy. Accord- ing to this hypothesis, the paracrine effect of FGF-23 may further lead to an increase in the ratio of FGF-23 to sKlotho locally and aggravate cardiac hypertrophy.26,43 To our knowledge, Klotho is not only a coreceptor of FGF-23 but also a con- verter of FGF-23/FGFR interaction. Mechanistically, FGF-23 has a higher affinity for FGFR-4 than for FGFR-1 in the absence of Klotho, but it shows a nearly 20-fold increase in affinity for FGFR-1 when Klotho is present.90 Recent studies have revealed that sKlotho acts as a coreceptor for FGF-2391 and a protective factor for the myocardium through “pathway conversion,” and these were previously considered as essential functions of mKlotho (Figure 3).12,42 Specific cardiac ablation of Fgfr-4 blocks FGF- 23–induced cardiac hypertrophy, and sKlotho administration converts FGF- 23–induced PLCg/calcineurin signaling into mitogen-activated protein kinase fi Figure 2. The cardiac effects of elevated FGF-23 is signi cantly different in CKD and (MAPK) signaling.42 In addition, sKlo- XLH. Increased FGF-23 is observed in both CKD and XLH. However, the increase in FGF-23 tho leads to only a small increase in ac- occurs secondary to hyperphosphatemia, whereas it is idiopathic and induces hypo- tivation of MAPK activity in response to phosphatemia in XLH. Elevated FGF-23 induces cardiac hypertrophy in CKD, whereas no 92 cardiac changes are observed in XLH. In CKD, perhaps the relative levels of circulating FGF-23, which means that this path- FGF-23 and phosphate determine the prohypertrophic effects of FGF-23. Moreover, it is way conversion may not induce robust unclear whether any other factors might affect the prohypertrophic effect of FGF-23. activation of MAPK signaling and result in cardiac hypertrophy. Unfortunately, however, these studies were not repro- sKlotho in human samples remains con- low-phosphate diet containing only 0.2% duced in CKD models. Theoretically, troversial. Thus, the association between inorganic phosphate does not block the high FGF-23 and low sKlotho levels in sKlotho and cardiovascular risk needs exacerbation of cardiac hypertrophy in CKD may lead to the interaction of FGF- careful consideration. CKD mice with heterozygous Klotho de- 23 and FGFR-4 and activate the calci- letion.66 Hence, the reduction in sKlotho neurin pathway, which can cause cardiac may be involved in CKD-induced cardiac hypertrophy.37 COMBINED CARDIAC EFFECTS OF hypertrophy regardless of FGF-23 level. FGF-23 AND KLOTHO IN CKD Six et al.89 found that Klotho deficiency is detrimental to the endothelium and that INDIRECT CARDIAC EFFECTS OF As a known scenario of cardiac hypertro- Klotho sufficiency prevents the damag- FGF-23 AND a-KLOTHO IN CKD phy, CKD is accompanied by a low level ing effects of FGF-23 and hyperphos- of sKlotho and a high level of FGF-23 in phate. In addition, Hu et al.58 revealed Effects on Vessels circulation.85,86 Although FGF-23 in- that a positive correlation between FGF- Vascular lesions, another pathologic fea- duces cardiac hypertrophy via FGFR-4 23 levels and cardiac hypertrophy and fi- ture of patients with CKD, are closely in the absence of Klotho,33,37 sKlotho brosis occurs only with relatively low related to cardiac impairment. Animal may exert cardioprotective effects with- sKlotho levels. Han et al.42 found that models or patients with genetic Klotho out the presence of FGF-23.68,77,87 sKlotho injection inhibits FGF-23– deficiency develop extensive arteriosclero- Whether an increased ratio of circulating induced cardiac hypertrophy, providing sis and vascular calcification, which are FGF-23 to sKlotho in CKD results in further evidence for the antihypertrophic similar to CKD-related vascular injury.14,93 more serious cardiac hypertrophy is effect of sKlotho. Collectively, we may in- In CKD mice, Klotho preservation not unknown.88 fer that beyond the levels of FGF-23 only attenuates hyperphosphatemia but It seems that normalization of cir- or sKlotho individually, the ratio of also suppresses the activity of the NaPi-3 culating FGF-23 and phosphate via a these two proteins is a key contributor groupofsodium-coupledtransporters

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In contrast, other work demonstrated that FGF-23 overexpression results in hypotension, and hypophosphatemia caused by high levels of circulating FGF-23 may mediate such BP de- creases.51 To illustrate this inconsistency, the balance in circulating levels of FGF- 23 and phosphate should be considered.

Effects on Immunocytes In recent years, inflammation has been considered as a consequence of disturbance of the FGF-23/Klotho axis,105 sug- gesting another way FGF-23 and Klotho can indirectly affect the heart. Elevated FGF-23 acts on FGFR-2 on neutrophils in the absence of Klotho; this deactivates b2-integrin and impairs recruitment of neutrophils to infection sites,106–108 which may partially explain the impaired host defense resulting from neutrophil dysfunction in patients with CKD. Studies also have demonstrated Figure 3. FGF-23 activates MAPK signaling in the presence of sKlotho, whereas acti- that FGF-23 inhibits the production of vates calcineurin signaling in the absence of sKlotho. (A) Under physiologic conditions, 1,25-dihydroxyvitamin D3 and results sKLOTHO functions as a coreceptor of FGF-23 and leads to MAPK signaling activation. in monocyte dysfunction (increasing sus- Importantly, sKlotho only leads to a small increase in activation of MAPK activity in re- ceptibility to bacterial infection)109 and sponse to FGF-23, which means it may not induce robust activation of MAPK signaling and macrophage activation,110 which are result in cardiac hypertrophy. (B) In CKD, decreased sKlotho blunts the interaction between closely related to chronic inflammation. FGF-23 and FGFR-1, and FGF-23 preferentially binds to FGFR-4, thus resulting in calci- In addition, FGF-23 promotes the release neurin cascade activation and pathologic cardiac hypertrophy. of proinflammatory factors in hepatocytes under CKD conditions and may partici- (Pit-1 and Pit-2), thus inhibiting calcifi- both FGFR-dependent ROS formation pate in chronic inflammation.111 cation and dedifferentiation of vascular via activation of NADPH oxidase 2, as Given Klotho’sroleasananti- smooth muscle cells.94 In addition, Klo- well as ROS degradation via activation inflammatory effector,112 its deficiency in tho deficiency is highly involved in endo- of SOD2 and catalase.96 However, the ab- CKD may also play a role in the generation thelial dysfunction, which is mediated sence of Klotho blunts FGF-23–induced of inflammation. The cardiovascular by increased apoptosis and reduced pro- eNOS, SOD2, and catalase generation, pathogenic role of chronic inflammation duction of endothelial nitric oxide synthase whereas FGF-23–induced ROS synthesis in CKD has been demonstrated113; hence, (eNOS).95–97 In vivo treatment with is unaffected.96 The balance between the the association between FGF-23 and in- Klotho leads to alleviation of endothelial generation and degradation of ROS may flammation may greatly enhance the sig- dysfunction, high BP, and perivascular be lost in CKD, thus leading to the suc- nificance of FGF-23 in uremic cardiac fibrosis.98 cessive production of ROS and vascular hypertrophy. It is not surprising that FGF-23 defi- injury. Therefore, FGF-23’s vascular ef- ciency results in a phenotype in blood fects, as they affect cardiomyocytes, are vessels similar to that of CKD-related vas- probably also determined by the ratio of SUMMARY AND FUTURE cular injury, given the disturbance in FGF-23 to sKlotho. PERSPECTIVES phosphate metabolism.99,100 Conversely, high circulating FGF-23 also results in vas- Effects on Kidney As endocrine factors, FGF-23 and Klo- cular injury. Studies in patients with CKD Elevated FGF-23 has been described as a tho exert effects on various tissues in the found that high FGF-23 is associated with hypertension-related factor, and studies absence or presence of one another. In vascular dysfunction.101–103 In endothelial suggest that prohypertensive effect may this review, we described the direct and cells, FGF-23/Klotho/FGFR-1 promotes partially be due to the increase in sodium indirect effects of FGF-23 and Klotho on the production of eNOS via the AKT- reabsorption via sodium chloride co- cardiac tissues, including hypertrophy- dependent pathway. FGF-23 stimulates transporters in the distal tubules.48,104 related effects, vessel-related effects,

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Figure 4. Direct and indirect effects of FGF-23 and KLOTHO on myocardium. In CKD, high FGF-23 level and Klotho/sKLOTHO deficiency lead to several changes in blood vessels, inflammatory responses, and the kidney, including vascular injury, inflammation, hypertension, and active 1,25-dihydroxyvitamin D3 (1,25-[OH]2-VitD3)deficiency. These changes can induce cardiac hypertrophy directly and indirectly. Moreover, disturbances in FGF-23/sKLOTHO may induce cardiac hypertrophy and fibrosis directly. 25-OH-VitD3, 25-hydroxyvitamin D3; 2 1 Cl ,chlorideion;Na , sodium ion.

JASN 31: 1423–1434, 2020 FGF-23 and Cardiac Hypertrophy 1429 REVIEW www.jasn.org and inflammation-related effects (Fig- response and promotes cardiac hyper- be a consequence of promoting the stress ure 4). However, in light of continuing trophy as a compensatory response re- response, although it reduces the excre- controversies regarding the cardiac ef- quires further study. tion of phosphate. fects of FGF-23 and Klotho, further in- According to current understanding, Collectively, we hypothesize that se- vestigations are needed. the FGF-23/Klotho axis interacts with vere hyperphosphatemia, hypophospha- The discrepancy in cardiac changes in the RAS44,50 and ROS,96 which are all temia, and a high circulating level of XLH and CKD is the most controversial constituents of the stress response. It is FGF-23 trigger the stress response, thus aspect of FGF-23–induced cardiac hy- possible that elevated FGF-23 in CKD downregulating Klotho/sKlotho and ul- pertrophy, and several mechanisms can act as a stress hormone, similar to timately enhancing the stress response. may account for this discrepancy. The another member of the FGF-19 subfam- The balance of FGF-23, sKlotho, and process of FGF-23 cleavage may explain ily, FGF-21,118,119 a speculation that can phosphate actually represents the degree this discordance. Under physiologic be partially verified in cardiomyocytes. of the stress response. Under this hy- conditions, iFGF-23 and its cleavage Incubation of cardiomyocytes with pothesis, FGF-23 is not a detrimental are in dynamic equilibrium, but in FGF-23 results not only in cardiomyo- factor for the heart but rather a hormone CKD, iFGF-23 cleavage may be im- cyte hypertrophy, but also augments the to induce the stress response and protect paired, leading to iFGF-23 accumulation contractility of cardiomyocytes, and the the body from injurious factors. In some and several pathologic changes.114–116 hypertrophic condition seems to be a disease states, such as pathologic cardiac Mechanistically, cFGF-23, which is the compensatory response for increased hypertrophy, the secretion of FGF-23 cleavage product of iFGF-23, can bind to contractility.120 An in vivo study further from damaged organs may represent a FGFR-1/Klotho competitively, thereby in- revealed that FGF-23–induced cardiac/ protective response.123 Obviously, how- hibiting hypophosphatemia induced by a cardiomyocyte hypertrophy is revers- ever, the continuous stress response high circulating level of iFGF-23.117 Arecent ible.121 This suggests that FGF-23– leads to organ damage, including cardiac study found that cFGF-23 attenuates fibro- induced hypertrophy is a reversible re- hypertrophy and vascular injury.124 Under sis and inflammation in diabetic nephrop- sponse to increased contractility, and the this scenario, persistent FGF-23/sKlotho athy, although the underlying mechanisms disappearance of the stressor (FGF-23) disturbance converts protective effects are not clear.7 It is possible that cFGF-23 results in a decreased stress response into detrimental effects. Thus, we suspect interferes with the interaction between (mitigation of cardiac hypertrophy). that the FGF-23/Klotho axis is closely re- FGF-23 and FGFR-4. Notably, the cleavage Moreover, FGF-23 upregulates the intra- lated to the stress response, and that elu- of iFGF-23 seems normal in XLH.45 Hence, cellular expression of Ang-II in cardiomyo- cidating the detailed relationship of the abnormal cleavage of iFGF-23 may contrib- cytes and shares a common mechanism of stress response and FGF-23/Klotho in ute to uremic cardiac hypertrophy. calcium-dependent cardiomyocyte hyper- uremic cardiac hypertrophy may offer a The largest difference between CKD trophy with Ang-II. This further indicates a new research direction. and XLH is that XLH exhibits significant close interaction of FGF-23 and the stress hypophosphatemia instead of hyper- response in cardiomyocytes.122 phosphatemia. Interestingly, overex- XLH is also an abnormal condition DISCLOSURES pression of FGF-23 leads to hypotension and can trigger a stress response as and cardiac hypertrophy, with activation well. Several studies reported a high All authors have nothing to disclose. of the renin-angiotensin system (RAS) rate of LVH in patients with XLH or and the sympathetic nervous system. XLH models.48–50 One possibility is The latter phenomena (cardiac hyper- that severe hypotension and hypophos- trophy and activation of the RAS and phatemia in XLH trigger a stress re- FUNDING sympathetic nervous system) are consid- sponse and strengthen FGF-23–induced ered a stress response to hypotension hypertrophy; in turn, FGF-23 enhances A. Li was supported by National Natural Science and can be mitigated by a high- the stress response, forming a positive Foundation of China grants 81270825 and phosphate diet.51 However, Pastor- feedback loop and ultimately leading to 81770727, Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme grant 45 fi Arroyo et al. observed hypotension in signi cant cardiac hypertrophy. CKD 2017, Science and Technology Planning Project of XLH models, but there were no cardiac can be regarded as a stress state, Guangdong Province grant 2017A010103041, and changes in these models. This inconsis- wherein the stress response aims to cor- Key Project of Guangzhou Science Technology and tency may be caused by different degrees rect manifestations of the disorder such Innovation Commission grant 201804020054. of stress responses due to genetic back- as hyperphosphatemia and uremic toxin ground (Table 1). As mentioned above, accumulation. 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