The role of klotho in chronic kidney disease

Abstract

Chronic kidney disease (CKD) is an inherently systemic disease that refers to a long-term loss of kidney function. The progression of CKD has repercussions for other organs, leading to many kinds of extrarenal complications. Intensive studies are now being undertaken to reveal the risk factors and pathophysiological mechanism of this disease. During the past 20 years, increasing evidence from clinical and basic studies has indicated that klotho, which was initially known as an anti-aging gene and is mainly expressed in the kidney, is significantly correlated with the development and progression of CKD and its complications. Here, we discuss in detail the role and pathophysiological implications of klotho in ion disorders, the inflammation response, vascular calcification, mineral bone disorders, and renal fibrosis in CKD. Based on the pathogenic mechanism of klotho deficiency and klotho decline in urine early in CKD stage 2 and even earlier in CKD stage 1, it is not difficult to understand that soluble klotho can serve as an early and sensitive marker of CKD. Moreover, the prevention of klotho decline by several mechanisms can attenuate renal injuries, retard CKD progression, ameliorate extrarenal complications, and improve renal function. In this review, we focus on the functions and pathophysiological implications of klotho in CKD and its extrarenal complications as well as its potential applications as a diagnostic and/or prognostic biomarker for CKD and as a novel treatment strategy to improve and decrease the burden of comorbidity in CKD.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…FGF-23 requires klotho protein as a co-receptor [70]. The full length klotho protein, which is predominantly expressed in the proximal and distal tubules of the kidneys [72], is cleaved and circulates as a soluble klotho fragment serving as a surrogate marker of renal klotho expression [70]. In the circulation, calciprotein particles (CPP) "capture" calcium (Ca) and P i with the help of the adipokine fetuin A and prevent the precipitation of Ca-P i [70,73].…”

“…When renal function declines, klotho levels decrease in humans and in rodents with CKD [70]. Klotho-overexpressing mice with CKD have an increased phosphaturia, as well as an improved renal function and EVA phenotype [72]. In mice with an ICR-derived glomerulonephritis, overexpression of the kl gene reduces blood urea nitrogen levels, proteinuria, renal SA-β-gal activity, and the development of glomerular and tubulointerstitial changes [108].…”

“…Kidney-derived klotho is of particular interest as a potential treatment for inflammation and premature ageing in CKD, because klotho-deficient mice and patients with CKD have similar phenotypes, such as EVA and a pro-inflammatory status, and klotho is related to ageing in both humans and mice [70,72]. Similar to the NRF2 system, klotho is repressed in CKD, and stimulation of klotho can ameliorate oxidative stress and mitochondrial function [108], renal fibrosis [152], inflammation [72], as well as premature ageing [108], including EVA [55,[81][82][83][111][112][113].…”

“…Therapeutic approaches to stimulate klotho expression can aim for the reactivation of endogenous klotho or the administration of exogenous klotho [72]. Several drugs increase endogenous klotho [72].…”

“…Therapeutic approaches to stimulate klotho expression can aim for the reactivation of endogenous klotho or the administration of exogenous klotho [72]. Several drugs increase endogenous klotho [72]. For instance, the thiazolidinedione pioglitazone protects against renal injury in ageing by an increased expression of klotho [72].…”