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Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy

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Fibroblast Growth Factor-23 and Uremic Cardiac Hypertrophy REVIEW www.jasn.org 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 func- tion 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 dem- onstrates 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 JASN 31: 1423–1434, 2020 ISSN : 1046-6673/3107-1423 1423 REVIEW www.jasn.org roidism lead to increased circulating levels of FGF-23. Often, worse kidney function is associated with higher circu- lating 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 cardiovas- cular 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. 1424 JASN JASN 31: 1423–1434, 2020 www.jasn.org REVIEW 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.
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