Transient receptor potential cation channel subfamily V member 5 and subfamily C member 6 pathway (TRPV5/TRPC6 pathway)

The TRPV5/TRPC6-related calcium channel pathway is a physiological network of ion channels primarily responsible for maintaining renal calcium homeostasis and glomerular integrity. Transient Receptor Potential Vanilloid 5 (TRPV5) acts as the rate-limiting step for active calcium reabsorption in the kidney distal convoluted tubule, ensuring systemic mineral balance (UniProt: Q9NZW9; Hoenderop et al., 2005). Transient Receptor Potential Canonical 6 (TRPC6) is a non-selective cation channel located in the podocytes of the glomerular filtration barrier, where it regulates cytoskeletal dynamics and cell signaling (UniProt: Q9Y210; Winn et al., 2005). Dysregulation of this pathway is a hallmark of several renal pathologies; for instance, gain-of-function mutations in TRPC6 lead to focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome due to podocyte overstimulation and death (Winn et al., 2005). Conversely, impaired TRPV5 function results in severe hypercalciuria and an increased risk of nephrolithiasis (Hoenderop et al., 2005). Pharmacological intervention in this pathway currently focuses on TRPC6 antagonists, such as BI 764198 and GFB-887, which aim to reduce proteinuria and preserve kidney function in patients with chronic kidney disease (NCT04176536; Goldfinch Bio). These therapies seek to restore the balance of ion flux within the nephron to prevent progressive tissue damage.

Other names

TRPV5-TRPC6 axisRenal calcium transport pathwayECAC1/TRP6 pathwayPodocyte TRP channel pathway

Inhibition of TRPC6-mediated cation influx to prevent podocyte injury and modulation of TRPV5-mediated calcium transport via Vitamin D receptor activation to maintain mineral balance.