Podocyte injury in diabetic nephropathy: implications of angiotensin II-dependent activation of TRPC channels.

Daria V Ilatovskaya,Oleg Palygin,Alexander Staruschenko,Leonid S Shuyskiy,Andrea Lowing,Vladislav Levchenko

doi:10.1038/srep17637

Abstract

Injury to podocytes is considered a major contributor to diabetic kidney disease: their loss causes proteinuria and progressive glomerulosclerosis. Podocyte depletion may result from improper calcium handling due to abnormal activation of the calcium permeant TRPC (Transient Receptor Potential Canonical) channels. Angiotensin II (Ang II) levels are found to be elevated in diabetes; furthermore, it was reported that Ang II causes activation of TRPC6 in podocytes. We hypothesized here that Ang II-mediated calcium influx is aggravated in the podocytes under the conditions of type 1 diabetic nephropathy (DN). Diabetes was induced in the Dahl Salt-Sensitive rats by an injection of streptozotocin (STZ-SS). Eleven weeks post treatment was sufficient for the animals to develop hyperglycemia, excessive urination, weight loss, microalbuminuria, nephrinuria and display renal histological lesions typical for patients with DN. Patch-clamp electrophysiology performed on podocytes of the freshly isolated glomeruli showed enhanced basal TRPC channel activity in the STZ-SS rats, and increased response to Ang II; total calcium influx triggered by Ang II application was also augmented in podocytes of these rats. Our studies have a strong potential for advancing the understanding of TRPC-mediated effects on podocytopenia in DN initiation.

Highlights

Found in the podocytes of patients and animals with proteinuric kidney disease[13,14]
The 6 week long protocol did not produce kidney damage characteristic of Diabetic nephropathy (DN), whereas 11 weeks of hyperglycemia resulted in significant glomeruli damage (Fig. 2a)
We report here our recent findings on the role of Ang II – dependent activation of the podocytic TRPC channels in the development of DN

Summary

Introduction

Found in the podocytes of patients and animals with proteinuric kidney disease[13,14]. Convincing studies reported that Ang II can aggravate albuminuria by activating TRPC6 channels in podocytes[22], and Ang II – induced podocyte apoptosis involves altered TRPC6 expression and Ca2+ influx[23]. In our recent publications using knockout animal models we demonstrated the Ang II – dependent up regulation of TRPC6 channels in the podocytes of freshly isolated glomeruli at the level of single ion channel activity[20]. The current study tests the long-term effects of Ang II on TRPC6 channels in a model of type 1 diabetes induced in Dahl SS rats with a single injection of STZ (further referred to as STZ-SS)[24]. The STZ-SS model in combination with unique electrophysiological approaches allowed us to measure single TRPC channel activity and live calcium concentration changes in the podocytes of the freshly isolated glomeruli. For the first time we demonstrated the enhanced TRPC-mediated calcium influx in response to Ang II in the podocytes undergoing DN-related pathological changes

Methods

Results

Conclusion