TRPC6, a Ca(2+)-permeable non-selective cation channel, is expressed in various tissues such as the brain, smooth-muscle-containing tissues, kidney, immune and blood cells [1,4]. It is directly activated by diacylglycerol (DAG), and regulated by tyrosine or serine phosphorylation. TRPC6 is involved in multiple physiological processes like smooth-muscle contraction, and is essential for the slit-diaphragm architecture of kidney podocytes [1,4]. Genetic models, especially knockout models, have been crucial in understanding its function.

Studies with TRPC6(-/-) mice suggest its role in regulating vascular and pulmonary smooth-muscle contraction [1]. In the context of kidney diseases, TRPC6 knockout has shown to reduce glomerular manifestations of disease in models of nephrotic syndromes, autoimmune glomerulonephritis, and renal fibrosis caused by urinary tract obstruction, but was less effective in reducing diabetic nephropathy in mouse and rat models [3]. In diabetic kidney disease mouse models, TRPC6-mediated calpain activation impairs podocyte autophagy, leading to injury and disease progression, indicating a potential therapeutic target by restoring autophagy [2].

In conclusion, TRPC6 plays essential physiological roles in smooth-muscle contraction and kidney podocyte function. The use of TRPC6 knockout mouse models has provided valuable insights into its role in kidney-related diseases, such as diabetic kidney disease, nephrotic syndromes, and renal fibrosis. These findings highlight the potential of targeting TRPC6 for therapeutic intervention in these disease areas.

References:

1. Dietrich, A, Gudermann, T. . TRPC6. In Handbook of experimental pharmacology, , 125-41. doi:. https://pubmed.ncbi.nlm.nih.gov/17217054/

2. Salemkour, Yann, Yildiz, Dilemin, Dionet, Léa, Tharaux, Pierre-Louis, Lenoir, Olivia. 2023. Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy. In Journal of the American Society of Nephrology : JASN, 34, 1823-1842. doi:10.1681/ASN.0000000000000212. https://pubmed.ncbi.nlm.nih.gov/37678257/

3. Dryer, Stuart E, Kim, Eun Young. 2022. The Effects of TRPC6 Knockout in Animal Models of Kidney Disease. In Biomolecules, 12, . doi:10.3390/biom12111710. https://pubmed.ncbi.nlm.nih.gov/36421724/

4. Dietrich, Alexander, Gudermann, Thomas. . TRPC6: physiological function and pathophysiological relevance. In Handbook of experimental pharmacology, 222, 157-88. doi:10.1007/978-3-642-54215-2_7. https://pubmed.ncbi.nlm.nih.gov/24756706/