Klotho May Ameliorate Proteinuria by Targeting TRPC6 Channels in Podocytes

Abstract

Klotho is a type-1 membrane protein predominantly produced in the kidney, the extracellular domain of which is secreted into the systemic circulation. Membranous and secreted Klotho protect organs, including the kidney, but whether and how Klotho directly protects the glomerular filter is unknown. Here, we report that secreted Klotho suppressed transient receptor potential channel 6 (TRPC6)-mediated Ca influx in cultured mouse podocytes by inhibiting phosphoinositide 3-kinase-dependent exocytosis of the channel. Furthermore, soluble Klotho reduced ATP-stimulated actin cytoskeletal remodeling and transepithelial albumin leakage in these cells. Overexpression of TRPC6 by gene delivery in mice induced albuminuria, and exogenous administration of Klotho ameliorated the albuminuria. Notably, immunofluorescence and in situ hybridization revealed Klotho expression in podocytes of mouse and human kidney. Heterozygous Klotho-deficient CKD mice had aggravated albuminuria compared with that in wild-type CKD mice with a similar degree of hypertension and reduced clearance function. Finally, disrupting the integrity of glomerular filter by saline infusion-mediated extracellular fluid volume expansion increased urinary Klotho excretion. These results reveal a potential novel function of Klotho in protecting the glomerular filter, and may offer a new therapeutic strategy for treatment of proteinuria.

Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

“…Interestingly, a recent paper reports that soluble FLT1 (the shed ectodomain of VEGF receptors) also regulates podocyte function by binding to GM3 in lipid rafts (22). We have also found that klotho is expressed in podocytes and protects podocytes against injury (23). Thus, gangliosides-enriched lipid rafts are important targets of extracellular factors with potentially important biological and disease significance.…”

Inhibition of TRPC6 channels ameliorates renal fibrosis and contributes to renal protection by soluble klotho

“…Yet, double Trpc3 and Trpc6 knockout confers the same degree of protection against kidney fibrosis as single Trpc6 knockout. These results suggest that TRPC3 and TRPC6 channels work in the same pathway, possibly in the context of formation of TRPC3/TRPC6 heteromultimers, 25,26 to contribute to the pathogenesis of fibrosis.…”

“…25,26 Both TRPC channel genes contain NFAT-responsive elements in their promoters that may lead to eedforward amplification of abnormal Ca 2+ signaling. Therefore, we examined the expression of TRPC3 and TRPC6 in UUO kidneys.…”

“…6 TRPC3 and TRPC6 channels are not only highly homologous in structure, but also share functional, regulatory and pharmacological similarities, as well as forming heteromultimers in some cell types. 25,26 A recent study using Trpc3 knockout mice and pharmacological blockage of TRPC3 in rats demonstrates an important role of TRPC3 in the pathogenesis of tubulointerstitial damage and renal fibrosis. 12 In the present study, we show that both TRPC3 and TRPC6 expression are markedly increased in UUO kidney.…”

Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria

“…A nephroprotective role has been demonstrated for Klotho in an animal model of type 1 diabetes, with global overexpression ameliorating the histological features of DKD and reducing albuminuria [9]. In a recent study using a non-diabetic animal model of albuminuria, treatment with exogenous soluble Klotho resulted in a reduction of urinary albumin excretion by protecting against podocyte injury [10].…”