Secreted Klotho and Chronic Kidney Disease

Abstract

Soluble Klotho (sKl) in the circulation can be generated directly by alterative splicing of the Klotho transcript or the extracellular domain of membrane Klotho can be released from membrane-anchored Klotho on the cell surface. Unlike membrane Klotho which functions as a coreceptor for fibroblast growth factor-23 (FGF23), sKl, acts as hormonal factor and plays important roles in anti-aging, anti-oxidation, modulation of ion transport, and Wnt signaling. Emerging evidence reveals that Klotho deficiency is an early biomarker for chronic kidney diseases as well as a pathogenic factor. Klotho deficiency is associated with progression and chronic complications in chronic kidney disease including vascular calcification, cardiac hypertrophy, and secondary hyperparathyroidism. In multiple experimental models, replacement of sKl, or manipulated up-regulation of endogenous Klotho protect the kidney from renal insults, preserve kidney function, and suppress renal fibrosis, in chronic kidney disease. Klotho is a highly promising candidate on the horizon as an early biomarker, and as a novel therapeutic agent for chronic kidney disease.

The Effects of Exercise and Antioxidant on Klotho Gene Expression During Oxidative Stress in Rat’s Cardiac Tissue

“…This is in agreement with Hu et al, [51] as they reported that oral administration of antioxidant (troglitazone: antidiabetic with antioxidant properties) for 10 weeks significantly upregulates renal Klotho mRNA expression in OLETF rats. Cheng et al, [52] also reported that the reduced expression of klotho in cultured renal tubular cells of Streptozotocin-induced diabetic rats was reversed by antioxidant (Tiron).…”

“…Cheng et al, [52] also reported that the reduced expression of klotho in cultured renal tubular cells of Streptozotocin-induced diabetic rats was reversed by antioxidant (Tiron). Hu et al 2012 [51] proposed that overexpression of PPAR-γ (Peroxisome proliferator-activated receptor gamma) can be the underlying mechanism of increased renal Klotho expression by Antioxidant. The last step was to study the effect of combined exercise training with vitamin E treatment for 8 weeks on HFD induced oxidative stress.…”

Research Advances on the Genetic Mechanism of Diabetic Nephropathy

“…Soluble a-klotho, which is derived from the proteolytic cleavage of the extracellular portion of the membrane-bound a-klotho, can be measured in blood, urine, and cerebrospinal fluid. Alternatively, soluble aklotho can be generated directly by the alternative splicing of the a-klotho transcript [11]. Soluble Klotho protein functions as paracrine or autocrine hormones, modulating positive interactions by FGF23, including anti-aging, insulin-like growth factors, and the suppression of PTH.…”

Alternative Splicing in CKD

“…The main function of transmembrane Klotho is as a coreceptor for fibroblast growth factor-23, however, sKlotho appears to have several paracrine and endocrine functions, including modulation of ion transport, Wnt signal transduction, antirenin-angiotensin system, antisenescence, and antioxidation. 43 Human patients with CKD in general exhibit reduced renal expression of Klotho, 44 as well as reductions in sKlotho. In an apparent controversy, a recent study demonstrated that plasma and urinary levels of sKlotho are significantly elevated in patients with type 2 diabetes and preserved renal function.…”