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Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.

ABSTRACT: Klotho is an antiaging protein which exerts known cardioprotection. In kidney, trans-membrane Klotho acts as essential co-receptor of fibroblast growth factor 23 (FGF23). In the heart, soluble Klotho (sKlotho) protects from systolic dysfunction independently of FGF23. Here, we analyzed the association of FGF23 and sKlotho upon progression of chronic heart failure (CHF) and analyzed Klotho expression in human hearts. Serum levels of sKlotho and FGF23 were measured in 287 patients with cardiomyopathy (CMP). Tissue samples from CMP (n?=?10) and healthy control hearts (n?=?10) were analyzed for Klotho mRNA and protein expression. Individuals in the first FGF23 tertile were 4.1 times more likely of freedom from death, heart transplantation or assist device implantation compared to third tertile. No relationship was found between sKlotho and the combined endpoint. Instead, Klotho mRNA encoding the full-length form was upregulated in human CMP hearts. Immunoblotting confirmed upregulation of sKlotho associated with increased expression of proteases involved in cleavage of Klotho suggesting rather local effects of Klotho in the heart. Therefore, we conclude that in contrast to FGF23, serum sKlotho is not associated with disease severity or progression in CHF. Instead, Klotho is expressed and upregulated in diseased hearts, suggesting local paracrine effects.

SUBMITTER: Poelzl G

PROVIDER: S-EPMC5976633 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.

Poelzl G G Ghadge S K SK Messner M M Haubner B B Wuertinger Ph P Griesmacher A A Doerler J J Ensinger C C Ulmer H H Zaruba M M MM

Scientific reports 20180530 1

Klotho is an antiaging protein which exerts known cardioprotection. In kidney, trans-membrane Klotho acts as essential co-receptor of fibroblast growth factor 23 (FGF23). In the heart, soluble Klotho (sKlotho) protects from systolic dysfunction independently of FGF23. Here, we analyzed the association of FGF23 and sKlotho upon progression of chronic heart failure (CHF) and analyzed Klotho expression in human hearts. Serum levels of sKlotho and FGF23 were measured in 287 patients with cardiomyopa ...[more]

PMID: 29849175

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Project description:The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability.

Project description:ObjectiveOur laboratory recently identified the centrally circulating ?-klotho protein as a novel hypothalamic regulator of food intake and glucose metabolism in mice. The current study aimed to investigate novel molecular effectors of central ?-klotho in the arcuate nucleus of the hypothalamus (ARC), while further deciphering its role regulating energy balance in both humans and mice.MethodsCerebrospinal fluid (CSF) was collected from 22 adults undergoing lower limb orthopedic surgeries, and correlations between body weight and ?-klotho were determined using an ?-klotho enzyme-linked immunosorbent assay (ELISA) kit. To investigate the effects of ?-klotho on energy expenditure (EE), 2-day intracerebroventricular (ICV) treatment was performed in diet-induced obesity (DIO) mice housed in TSE Phenomaster indirect calorimetry metabolic cages. Immunohistochemical staining for cFOS and patch clamp electrophysiology were used to determine the effects of central ?-klotho on proopiomelanocortin (POMC) and tyrosine hydroxylase (TH) neurons. Additional stainings were performed to determine novel roles for central ?-klotho to regulate non-neuronal cell populations in the ARC. Lastly, ICV pretreatment with fibroblast growth factor receptor (FGFR) or PI3kinase inhibitors was performed to determine the intracellular signaling involved in ?-klotho-mediated regulation of ARC nuclei.ResultsObese/overweight human subjects had significantly lower CSF ?-klotho concentrations compared to lean counterparts (1,044 ± 251 vs. 1616 ± 218 pmol/L, respectively). Additionally, 2 days of ICV ?-klotho treatment increased EE in DIO mice. ?-Klotho had no effects on TH neuron activity but elicited varied responses in POMC neurons, with 44% experiencing excitatory and 56% experiencing inhibitory effects. Inhibitor experiments identified an ?-klotho?FGFR?PI3kinase signaling mechanism in the regulation of ARC POMC and NPY/AgRP neurons. Acute ICV ?-klotho treatment also increased phosphorylated ERK in ARC astrocytes via FGFR signaling.ConclusionOur human CSF data provide the first evidence that impaired central ?-klotho function may be involved in the pathophysiology of obesity. Furthermore, results in mouse models identify ARC POMC neurons and astrocytes as novel molecular effectors of central ?-klotho. Overall, the current study highlights prominent roles of ?-klotho?FGFR?PI3kinase signaling in the homeostatic regulation of ARC neurons and whole-body energy balance.

Dataset Information

Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.

Publications

Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.

Similar Datasets

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