αKlotho and Chronic Kidney Disease

Abstract

Alpha-Klotho (αKlotho) protein is encoded by the gene, Klotho, and functions as a coreceptor for endocrine fibroblast growth factor-23. The extracellular domain of αKlotho is cleaved by secretases and released into the circulation where it is called soluble αKlotho. Soluble αKlotho in the circulation starts to decline in chronic kidney disease (CKD) stage 2 and urinary αKlotho in even earlier CKD stage 1. Therefore soluble αKlotho is an early and sensitive marker of decline in kidney function. Preclinical data from numerous animal experiments support αKlotho deficiency as a pathogenic factor for CKD progression and extrarenal CKD complications including cardiac and vascular disease, hyperparathyroidism, and disturbed mineral metabolism. αKlotho deficiency induces cell senescence and renders cells susceptible to apoptosis induced by a variety of cellular insults including oxidative stress. αKlotho deficiency also leads to defective autophagy and angiogenesis and promotes fibrosis in the kidney and heart. Most importantly, prevention of αKlotho decline, upregulation of endogenous αKlotho production, or direct supplementation of soluble αKlotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiac function and morphometry, and alleviation of vascular calcification in CKD. Therefore in rodents, αKlotho is not only a diagnostic and prognostic marker for CKD but the enhancement of endogenous or supplement of exogenous αKlotho are promising therapeutic strategies to prevent, retard, and decrease the comorbidity burden of CKD.

Long noncoding RNA NEAT1 is involved in the protective effect of Klotho on renal tubular epithelial cells in diabetic kidney disease through the ERK1/2 signaling pathway

“…reported that the prevention of Klotho decline and direct supplementation of soluble Klotho are both associated with attenuated renal fibrosis and slowed chronic kidney disease (CKD) progression 24 . However, the effect of Klotho in DKD needs further study.…”

Relationship of Serum Soluble Klotho Levels and Echocardiographic Parameters in Patients on Maintenance Hemodialysis

“…Clinically, uremic cardiomyopathy is characterized by cardiac arrest or sudden death, left ventricular hypertrophy, cardiac fibrosis, congestive heart failure, and so on [4-6]. In addition to traditional risk factors such as smoking, hypertension, diabetes, anemia, and volume overload, Klotho deficiency also plays an important role because soluble Klotho (s-Klotho) is a circulating substance exerting multiple systemic biological actions on distant organs, such as directly protecting cells against a variety of insults including hypoxia, hyperoxia, oxidative stress, and cytotoxic medication and suppressing apoptosis [6, 7]. …”

Fibroblast Growth Factor 23 and Klotho in AKI

“…13 Klotho also directly can promote the internalization and degradation of the NaPi2a cotransporter in the renal proximal tubules. 56 Klotho also may be a suppressor of vitamin D signaling, 57,58 because klotho knockout mice can be rescued from a phenotype of soft-tissue calcification by deletion of the CYP27B1 gene. 59 Finally, klotho has myriad pleotropic actions as an inhibitor of apoptosis, fibrosis, and cell senescence, and as an up-regulator of autophagy.…”

“…Renal klotho expression and soluble levels of klotho in the blood and urine are decreased in animals and humans with CKD resulting from a variety of etiologies, including glomerular and tubulointerstitial diseases, diabetic nephropathy, subtotal nephrectomy, and others (reviewed by Neyra and Hu 58 ). Because the kidneys are the primary source of soluble klotho, it is perhaps unsurprising that circulating levels of soluble klotho decrease as CKD progresses.…”