Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

Significance: Regulation of Ca²⁺ signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca²⁺-conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca²⁺ signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage. Critical Issues: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases. Future Directions: Although it is evident that ROS regulate TRPC6-mediated Ca²⁺ signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748.