Differential Regulatory Role of Soluble Klothos on Cardiac Fibrogenesis in Hypertension

Liu, Xue; Chen, Yuanjian; McCoy, Cody; Zhao, Tian; Quarles, L. Darryl; Pi, Min; Bhattacharya, Syamal K.; King, Gwendalyn D.; Sun, Yao

doi:10.1093/ajh/hpw062

Cited by 20 publications

(20 citation statements)

References 39 publications

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“…Nevertheless, our findings provide additional insights into the pathophysiology of FGF23 and α-Klotho by suggesting that the levels of sKL as well as the tissue expression of mKL 135 , along with levels of circulating FGF23, may determine whether physiological or adverse effects are observed. For example, other studies show that angiotensin II can both enhance cardiac fibrosis (76) and attenuate cardiac hypertrophy in Kl Tg mice (59), possibly due to different roles of membrane and soluble α-Klotho isoforms. Typically, models of FGF23-induced LVH have suppression of α-Klotho (77), suggesting that cardiotoxicity requires elevated FGF23 and reduced sKL.…”

Section: Discussionmentioning

confidence: 99%

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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“…62 The cardioprotective effects of a-Klotho, however, are controversial, and transgenic mice with the global overexpression of transmembrane a-Klotho resulted in worsening of Ang II-induced cardiomegaly. 58,63 The opposite cardiovascular effects of Klotho may reflect differences in the functions of transmembrane a-Klotho, acting as an FGFR cofactor, and the hormonal actions of sKl that are FGFR independent. 64 Regardless, the respective pathogenic roles of hypertension and sKl-dependent upregulation of TRPC6 in the cardiomyocytes of FGFR1 DT cKO mice remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene

Han

Ross²,

Kolumam³

et al. 2017

JASN

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The bone-derived hormone fibroblast growth factor-23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and -Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of in the DT ( mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of -Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na-K-2Cl cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of -Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the mouse model of excess FGF-23, but did not induce a response in mice. The hearts of mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.

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“…Formalin-fixed paraffin-embedded heart tissue samples were deparaffinized in xylene, hydrated through a series of graded alcohols. For the quantification of cardiac myocyte size, fixed cardiac mid-chamber (MC) ( 33 ) sections were incubated with wheat germ agglutinin (WGA) Alexa Fluor555 (Invitrogen) at 5 µg/mL in PBS for 1 h to visualize cellular borders of individual cardiac myocytes. 4′,6-diamidino-2-phenylindole (DAPI; 0.2 µg/mL) was used for nuclear staining in the dark for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…Besides high FGF23 levels, klotho deficiency also seems to be associated with cardiac dysfunction in humans and rodents ( 25 , 29 , 31 ), and rescuing the availability of klotho by genetic overexpression or intravenous delivery of soluble klotho shows beneficial outcomes including amelioration of cardiac hypertrophy in klotho-deficient uremic mice and suppression of cardiac fibroblast activation and collagen synthesis ( 31 – 33 ). In addition, klotho ameliorates FGF23-mediated oxidative stress by inducing nitric oxide synthesis and degrading reactive oxygen species in endothelial cells ( 34 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

et al. 2018

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Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic (kl/kl) mice and Hyp mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated in vitro. Kl/kl mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including Rcan1, bMHC, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-β1, collagen I, and Mmp2 in kl/kl mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal klotho expression, Hyp mice showed no signs of pathological cardiac remodeling. Kl/kl mice showed enhanced serum calcium and phosphate levels, while Hyp mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous Fgf23 mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that Hyp mice, in contrast to kl/kl mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia.

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Differential Regulatory Role of Soluble Klothos on Cardiac Fibrogenesis in Hypertension

Cited by 20 publications

References 39 publications

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

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