Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate

Abstract

Cardiac hypertrophy occurs in up to 95% of patients with CKD and increases their risk for cardiovascular death. In the kidney, full-length membranous Klotho forms the coreceptor for fibroblast growth factor 23 (FGF23) to regulate phosphate metabolism. The prevailing view is that the decreased level of Klotho in CKD causes cardiomyopathy through increases in serum FGF23 and/or phosphate levels. However, we reported recently that soluble Klotho protects against cardiac hypertrophy by inhibiting abnormal calcium signaling in the heart. Here, we tested whether this protective effect requires changes in FGF23 and/or phosphate levels. Heterozygous Klotho-deficient CKD mice exhibited aggravated cardiac hypertrophy compared with wild-type CKD mice. Cardiac magnetic resonance imaging studies revealed that Klotho-deficient CKD hearts had worse functional impairment than wild-type CKD hearts. Normalization of serum phosphate and FGF23 levels by dietary phosphate restriction did not abrogate the aggravated cardiac hypertrophy observed in Klotho-deficient CKD mice. Circulating levels of the cleaved soluble ectodomain of Klotho were lower in wild-type CKD mice than in control mice and even lower in Klotho-deficient CKD mice. Intravenous delivery of a transgene encoding soluble Klotho ameliorated cardiac hypertrophy in Klotho-deficient CKD mice. These results suggest that the decreased level of circulating soluble Klotho in CKD is an important cause of uremic cardiomyopathy independent of FGF23 and phosphate, opening new avenues for treatment of this disease.

Phosphate Toxicity in CKD: The Killer among Us

“…With regard to cardiovascular dysfunction, Xie et al (133) showed that soluble Klotho protects the heart against stress-induced cardiac hypertrophy by inhibiting abnormal calcium signaling. Additional studies showed that intravenous delivery of a transgene coding for soluble Klotho protects against cardiomyopathy in Klotho-deficient CKD mice in a manner independent of FGF23 or phosphate (134). Intraperitoneal administration of Klotho protein to Klotho-deficient mice extended lifespan and attenuated systemic calcification and renal fibrosis; the protective effect on renal function was via downregulation of renal TGF-b mRNA expression, a main regulator of renal fibrosis (135).…”

Loss of Klotho in CKD Breaks One’s Heart

“…Some would say this association between low eGFR and a higher risk of death "from a broken heart" is already well appreciated by the nephrology community. 4 As might be expected, in the Alberta study, after adjustment for age and sex, 33% of deaths were attributed to cardiovascular disease when the eGFR was 45-59 ml/min per 1.73 m 2 , and 40% of deaths were attributed to cardiovascular disease when the eGFR was 15-29 ml/min per 1.73 m 2 . 3 Similarly, in the Ohio study, the 3-year probability of mortality from cardiovascular disease increased in a graded manner as eGFR declined (from approximately 3% when the eGFR was 60 ml/min per 1.73 m 2 to 7.5% when the eGFR was 10 ml/min per 1.73 m 2 ).…”

“…12 However, recent studies show that normalization of serum phosphate and FGF-23 levels fails to abrogate cardiac hypertrophy in Klotho-deficient CKD mice, suggesting that Klotho prevents uremic cardiomyopathy by a mechanism independent of FGF-23 and phosphate. 4 These observations together with the study by Yang et al 6 underscore that the cardioprotection of Klotho is most likely mediated by its direct action on cardiomyocytes. Indeed, although the molecular details remain to be delineated, Klotho was shown to prevent IS-induced, ROS-mediated MAPK activation and cell hypertrophy in cultured cardiac myocytes.…”

“…There are a variety of uremia-specific nontraditional risk factors in CKD that may be implicated in the pathogenesis of cardiovascular complications, including the presence of proteinbound uremic toxins, such as indoxyl sulfate (IS), low serum level of Klotho, albuminuria, hyperactive renin-angiotensinaldosterone system (RAAS), and abnormal bone and mineral metabolism. [3][4][5] Systematic delineation of the relative importance and complex interaction of these risk factors for CVD in patients with CKD is a daunting task, but such knowledge is necessary and paramount in developing effective strategies for alleviating CKD-associated cardiovascular complications in the clinical setting.In this issue of JASN, Yang et al 6 investigated the potential role and mechanisms of antiaging protein Klotho in ameliorating IS-induced myocardial hypertrophy. By analyzing clinical data, Yang et al 6 showed that, in a cohort of 86 patients with CKD, there was an inverse correlation between serum levels of IS and Klotho.…”

Genetics of aging and longevity

“…Коррекция уровня фосфатов и витамина D предотвращает преждевременное старение, что является одним из воз-можных механизмов геропротекторного действия Klotho (Bian et al, 2015). Имеются данные о том, что повышение активности Klotho с помощью генной терапии увеличи-вает продолжительность жизни и улучшает показатели здоровья у животных с нехваткой Klotho (Wang, Sun, 2014;Xie et al, 2015).…”