TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases

Abstract

Podocytes (terminally differentiated epithelial cells of the glomeruli) play a key role in the maintenance of glomerular structure and permeability and in the incipiency of various renal abnormalities. Injury to podocytes is considered a major contributor to the development of kidney disease as their loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium handling; excessive calcium influx in these cells may result in the effacement of foot processes, apoptosis, and subsequent glomeruli damage. One of the key proteins responsible for calcium flux in the podocytes is transient receptor potential cation channel, subfamily C, member 6 (TRPC6); a gain-of-function mutation in TRPC6 has been associated with the onset of the familial forms of focal segmental glomerulosclerosis (FSGS). Recent data also revealed a critical role of this channel in the onset of diabetic nephropathy. Therefore, major efforts of the research community have been recently dedicated to unraveling the TRPC6-dependent effects in the initiation of podocyte injury. This mini-review focuses on the TRPC6 channel in podocytes and colligates recent data in an attempt to shed some light on the mechanisms underlying the pathogenesis of TRPC6-mediated glomeruli damage and its potential role as a therapeutic target for the treatment of chronic kidney diseases.

Keywords: TRPC6; diabetic nephropathy; glomerulosclerosis; glomerulus; intracellular calcium; podocyte; proteinuria.

Fig. 1.

Effects of ANG II on transient receptor potential cation channel, subfamily C, member 6 (TRPC6) channel activity and calcium influx in the podocytes. A, left: representative current traces demonstrating the effects of ANG II on TRPC6 channel activity recorded in cell-attached patches made on podocytes of the freshly isolated glomeruli obtained from wild-type (WT) and TRPC6^−/− mice. Continuous current traces and addition of ANG II (1 μM) to the external bath solution are shown. All patches were held at a −60-mV test potential during the course of the experiment. The c and o_i denote closed and open current levels, respectively (adapted from Ref. 29). Right, top row: representative images of WT mouse glomeruli stained with Fluo4 (green pseudocolor) and Fura Red (red) before and after application of 1 μM ANG II; podocytes are marked with arrows. Note an increase in green signal and a decrease in red signal intensities upon addition of ANG II, which reflect an elevation in the intracellular calcium concentration. Bottom row: graphs demonstrate representative calcium transients caused by the application of 1 μM ANG II to the podocytes in WT and TRPC6^−/− mouse glomeruli. Scale bar = 30 μm. B: scheme illustrating podocyte retraction as a result of the excessive calcium influx through the TRPC6 channels under a pathological stimulus (elevated ANG II levels) originating in a disease condition. ROS, reactive oxygen species; ATR, ANG II receptor.