Role of TRPC6 in kidney damage after acute ischemic kidney injury

Zhihuang Zheng,Bernd Nürnberg,Xiaoning Chai,Michael Schaefer,Theda Ulrike Patricia Bartolomaeus,Cem Erdogan,May-Britt Köhler,Gabriele N’Diaye,Lajos Markó,Ute Krügel,Kaiyin Wu,Friedrich-Alexander Ludwig,Johanna Schleifenbaum,Maik Gollasch,Dmitry Tsvetkov

doi:10.1038/s41598-022-06703-9

Abstract

Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca2+ and other monovalent cations into cells, is widely expressed in the kidney. TRPC6 gene variations have been linked to chronic kidney disease but its role in acute kidney injury (AKI) is unknown. Here we aimed to investigate the putative role of TRPC6 channels in AKI. We used Trpc6−/− mice and pharmacological blockade (SH045 and BI-749327), to evaluate short-term AKI outcomes. Here, we demonstrate that neither Trpc6 deficiency nor pharmacological inhibition of TRPC6 influences the short-term outcomes of AKI. Serum markers, renal expression of epithelial damage markers, tubular injury, and renal inflammatory response assessed by the histological analysis were similar in wild-type mice compared to Trpc6−/− mice as well as in vehicle-treated versus SH045- or BI-749327-treated mice. In addition, we also found no effect of TRPC6 modulation on renal arterial myogenic tone by using blockers to perfuse isolated kidneys. Therefore, we conclude that TRPC6 does not play a role in the acute phase of AKI. Our results may have clinical implications for safety and health of humans with TRPC6 gene variations, with respect to mutated TRPC6 channels in the response of the kidney to acute ischemic stimuli.

Highlights

Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca2+ and other monovalent cations into cells, is widely expressed in the kidney
Transient receptor potential canonical or classical 6 (TRPC6) are non-selective Ca2+ permeable cation channels expressed in renal tissue including glomerular podocytes, mesangial cells, endothelial cells, tubulointerstitial vascular and epithelial cells, as well as in renal blood vessels4. Ca2+ influx through TRPC6 maintains the integrity of glomerular filtration barrier by interacting with nephrin, podocin, CD2-associated protein, and α-actinin-4 directly or indirectly[5]
To examine a possible role of Trpc[6] deficiency in acute kidney injury (AKI), we performed comparative in vivo studies using Trpc6−/− and WT mice (Fig. 1A)

Summary

Introduction

Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca2+ and other monovalent cations into cells, is widely expressed in the kidney. Transient receptor potential canonical or classical 6 (TRPC6) are non-selective Ca2+ permeable cation channels expressed in renal tissue including glomerular podocytes, mesangial cells, endothelial cells, tubulointerstitial vascular and epithelial cells, as well as in renal blood vessels. Shen et al found that silencing TRPC6 could prevent necroptosis of renal tubular epithelial cells upon IRI21 These findings indicate that inhibition of TRPC6 may protect the kidney from IRI making it a promising target to ameliorate AKI. We conclude that neither lacking nor pharmacological inhibition of TRPC6 ameliorates short-term outcomes of AKI

Objectives

Methods

Results

Conclusion