The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

Abstract

Renal ischemia/reperfusion (I/R), a major cause of acute kidney injury (AKI), is a serious clinical event in patients during post-renal transplantation. I/R is associated with renal dysfunction and tubular apoptosis, and calcium (Ca2+) overload has been reported to be a crucial factor on tubular apoptosis in I/R injury (IRI). The canonical transient receptor potential channel 6 (TRPC6), a type of non-selective Ca2+ channel, is involved in many renal diseases. Our earlier study identified that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in primary tubular epithelial cells (TECs). This study explored the potential beneficial impact of TRPC6 knockout (TRPC6−/−) and the relevant cellular mechanisms against I/R-induced AKI in mice. Measuring changes of renal function, apoptotic index, and autophagy in mouse kidneys that suffered 24 h reperfusion after 40 min ischemia and working in vitro with TECs that suffered 24 h reoxygenation after 24 h hypoxia, we found that 1) IRI tissues had increased TRPC6 expression and TRPC6 knockout significantly ameliorated renal damage induced by IRI; 2) TRPC6 knockout enhanced the level of autophagy and alleviated the depolarization of mitochondrial membrane potential (ψm, MMP) and apoptotic changes upon IRI; and 3) IRI tissues had increased p-AKT and p-ERK1/2 expressions, while TRPC6 knockout could markedly reduce the phosphorylation of AKT and ERK1/2. These discoveries suggest that, by reducing Ca2+ overload, the underlying protective mechanism of TRPC6−/− may be involved in down-regulation of PI3K/AKT and ERK signaling, which is likely to provide a new avenue for future AKI therapies.

Identification of hub genes associated with acute kidney injury induced by renal ischemia–reperfusion injury in mice

“…A previous study observed that IRI gave rise to phosphorylation of AKT in WT mice; subsequently, they utilized the inhibitors of AKT (MK2206) to reconfirm the signaling pathways involved in apoptosis regulation in hypoxia-reoxygenated human TECs. In agreement with IRI, it was observed that the phosphorylation of AKT was dramatically reduced (Hou et al, 2021). These results are consistent with our research results, indicating that the TNF, PI3K-Akt, and MAPK signaling pathways are critical in the mechanism of AKI induced by ischemia-reperfusion.…”

TRPC6 Is Found in Distinct Compartments of the Human Kidney

“…TRPC6-driven Ca 2+ influx inhibits autophagy and induces apoptosis via the activation of PI3K/AKT and ERK signaling pathways, ultimately leading to cytochrome c release in the cytosol and the high production of cytotoxic ROS. Indeed, in tubular epithelial cells from mice with TRPC6 knockdown, cytoprotective autophagy is activated, bypassing the apoptosis pathway [22,32,33].…”

TRPC6 inhibits renal tubular epithelial cell pyroptosis through regulating zinc influx and alleviates renal ischemia–reperfusion injury

“…The OGD/R model is often used to simulate the pathological process of ischemia and reperfusion in vitro. 13 To further study the effects of TRPC6 in I/R injury, HK-2 cell, an immortalized renal tubular epithelial cell line, was used to establish the OGD/R model. Blank shRNA and TRPC6 shRNA plasmids were constructed and transfected into HK-2 cells, and the transfected cells were used for experiments.…”

“…Canonical transient receptor potential channels (TRPCs), as a member of the TRP superfamily, are receptor‐activated and nonselective cation channels that are involved in a variety of life processes of cells 6 . TRPC6, belonging to the TRPC family, has been reported to play key roles in interstitial renal fibrosis, myocardial infarction, pulmonary hypertension, atherosclerosis, vascular embolic disease, diabetic nephropathy, and cancers, etc 6–13 . As a nonselective ion channel, apart from calcium ions, TRPC6 can also promote the influx of zinc ions 14 .…”