The novel role of TRPC6 in vitamin D ameliorating podocyte injury in STZ-induced diabetic rats

Abstract

Podocyte injury plays a critical role in the development and progression of diabetic nephropathy (DN). Over expression of TRPC6 on the podocytes has been revealed to cause podocyte injury in non-diabetic states. Besides, the emerging evidence from clinic revealed that vitamin D could reduce albuminuria and improve renal function, which was associated with podocyte protection. Our study aimed to investigate whether calcitriol ameliorating podocyte impairment is associated with regulation of the expression of TRPC6 in STZ-induced rats. Sprague-Dawley rats were randomly divided into three groups: normal control, DN, and DN treated with calcitriol (DN + VD); VD rats were treated with 0.1 μg/kg/d calcitriol by gavage. DN model rats were established by intraperitoneal injections of streptozocin. The rats were sacrificed after 18 weeks treatment. DN rats exhibited increased proteinuria accompanied by elevated TRPC6 expression. Treatment with calcitriol not only reduced proteinuria, but also normalized TRPC6 expression. Meanwhile, in DN rats, the expression of podocyte specific markers including nephrin and podocin was significantly decreased, accompanied by increased desmin, a marker of podocyte injury. Treatment with calcitriol reversed above changes. In addition, vitamin D receptor (VDR) was significantly decreased, whereas this reduction was attenuated by the calcitriol treatment. Moreover, TRPC6 was positively correlated with both 24 h urinary protein and desmin. In contrast, TRPC6 was negatively correlated with both VDR and nephrin expression in podocytes. Calcitriol can ameliorate podocyte injury, which is contributed by the inhibition of enhanced TRPC6 expression in the early stages of DN rats.

Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFκB Activation in Mouse Podocytes

“…The findings are principally in agreement with our data because retention of the NFκB subunits in the cytoplasma by prolonged binding to IκB-α subsequently destroys NFκB dimers [28]. Podocytes are apparently an important target of vitamin D3 and the hormone influences structure and function of podoyctes through various molecular mechanism [29,30,31,32]. In addition, activation of the NFκB-signaling pathway plays a major role in podocyte apoptosis [33,34,35], a pivotal feature of DN.…”

Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease

“…61 This observation is consistent with many studies showing that VDR activators are renoprotective in models of proteinuric CKD. 123-125 In glomerular diseases, activation of VDR inhibits expression Wnt/β-catenin target genes such as Snail1 and TRPC6 , prevents podocyte injury and reduces proteinuria. 61,125 The VDR-mediated sequestration of β-catenin might therefore contribute to the renal protection of vitamin D analogues in proteinuric CKD.…”

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

“…It has been widely reported that glomerular TRPC6 channels are substantially more abundant in type 1 and type 2 diabetes and in podocytes cultured in the presence of elevated external glucose . This is due at least in part to oxidative stress that can be driven by hyperglycemia, and by the surrounding pro‐inflammatory milieu .…”