TRPC6, a Ca(2+)-permeable non-selective cation channel, is expressed in various tissues like brain, smooth muscle-containing tissues, kidney, immune and blood cells [1,5]. It belongs to the DAG-activated subfamily of channels and might also be a mediator in the store-operated calcium entry pathway [2]. TRPC6 channels have a characteristic doubly rectifying current-voltage relationship, with six-fold higher permeability for Ca2+ than Na+ [1,5]. Given its expression pattern, it is likely involved in multiple physiological processes [1,5].

Studies with TRPC6(-/-) mice suggest its role in regulating vascular and pulmonary smooth muscle contraction [1]. In the kidney, TRPC6 is an essential component of the slit diaphragm architecture of podocytes [1,5]. Mutations and over-activation of TRPC6 lead to glomeruli injury. In diabetic kidney disease (DKD) models, factors like angiotensin II and reactive oxygen species stimulate calcium influx through TRPC6, causing podocyte hypertrophy and foot process effacement, and ultimately albuminuria and renal injury [3]. TRPC6 knockout has been shown to reduce glomerular manifestations of disease in some models and renal fibrosis caused by urinary tract obstruction, but is less effective in reducing DKD in mouse and rat models [4].

In conclusion, TRPC6 plays crucial physiological roles in smooth muscle contraction and kidney function. Model-based research, especially using TRPC6 knockout mouse models, has revealed its significance in diseases such as DKD, highlighting its potential as a therapeutic target for renal-related disorders.

References:

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

2. Jardin, Isaac, Nieto, Joel, Salido, Ginés M, Rosado, Juan A. 2020. TRPC6 channel and its implications in breast cancer: an overview. In Biochimica et biophysica acta. Molecular cell research, 1867, 118828. doi:10.1016/j.bbamcr.2020.118828. https://pubmed.ncbi.nlm.nih.gov/32822726/

3. Staruschenko, Alexander, Spires, Denisha, Palygin, Oleg. 2019. Role of TRPC6 in Progression of Diabetic Kidney Disease. In Current hypertension reports, 21, 48. doi:10.1007/s11906-019-0960-9. https://pubmed.ncbi.nlm.nih.gov/31115705/

4. 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/

5. 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/