Klotho Ameliorates Podocyte Injury through Targeting TRPC6 Channel in Diabetic Nephropathy

Abstract

Podocyte damage is vital for the etiopathogenesis of diabetic nephropathy (DN). Klotho (KL), a multifunctional protein, has been demonstrated to have renoprotective effects; nevertheless, the mechanism for protective effect has not been completely elucidated. Transient receptor potential cation channel subfamily C, member 6 (TRPC6), a potential target of KL, is implicated in glomerular pathophysiology. Here, we sought to determine whether KL could protect against podocyte injury through inhibiting TRPC6 in DN. We found that high glucose (HG) triggered podocyte injury as manifested by actin cytoskeleton damage along with the downregulation of KL and Synaptopodin and the upregulation of TRPC6. KL overexpression reversed HG-induced podocytes injury, whereas cotreatment with TRPC6 activator flufenamic acid (FFA) significantly abrogated the beneficial effects conferred by KL. Moreover, KL knockdown in podocytes resulted in actin cytoskeleton impairment, decreased Synaptopodin expression, and increased TRPC6 expression. In db/db mice, KL overexpression inhibited TRPC6 expression and attenuated diabetes-induced podocyte injury, which was accompanied by decreased albuminuria and ameliorated glomerulosclerosis. Our data provided novel mechanistic insights for KL against DN and highlighted TRPC6 as a new target for KL in podocytes to prevent DN.

Klotho Stabilizes the Podocyte Actin Cytoskeleton in Idiopathic Membranous Nephropathy through Regulating the TRPC6/CatL Pathway

“…Nonspecific overexpression of TRPC6 in mice has been linked to transient proteinuria [ 35 ]. Increased TRPC6 expression has also been observed in the renal tissues of IMN nephropathy patients and animal models [ 36 ]. TRPC6 expression plays a pivotal role in podocyte injury.…”

“…Consequently, Klotho may be an effective target for the treatment of podocyte injury and confer renoprotection. An accumulating body of evidence supports the renoprotective effects of Klotho in diabetic podocytes [10][11][12][13]. However, it remains unclear whether Klotho can mitigate C5b-9-induced podocyte injury and stabilize the podocyte cytoskeleton in IMN.…”

Cytoskeleton Rearrangement in Podocytopathies: An Update

“…It restored the expression of nephrin and ZO-1 and attenuated the increased TRPC6 expression [ 218 ]. A subsequent study found that klotho protected against podocyte cytoskeleton disruption and podocyte injury in DKD by significantly inhibiting the expression of TRPC6 [ 219 ]. These studies provide evidence that klotho is a potential therapeutic strategy for treating DKD by preserving the podocyte cytoskeleton.…”

2012-2022 TRPC6 channel and podocyte research trends: A bibliometric study

“…Glucose causes diabetic nephropathy by activating the renin-angiotensin system, leading to glomerular foot cell damage [40].Another similarly argues that the angiotensin II/TRPC6/NFAT axis is the treatment for diabetic nephropathy [41].KL inhibits TRPC6 expression, attenuates glycogenic kidney podocyte injury, and reduces proteinuria [42].…”