Nephrotic syndrome is a kidney disorder characterized by high urinary protein and low serum albumin caused by the impairment of glomerular podocytes. It has been reported that Transient Receptor Potential Canonical 6 (TRPC6) mutations found in patients with focal segmental glomerulosclerosis (FSGS) often cause hyperactivated channel currents. Regarding this mechanism, we have previously shown that the disruption of Calmodulin-mediated Ca²⁺-dependent inactivation in TRPC6 channel led to prolonged cation influx and disorganized cytoskeleton in the podocytes. Aside from this, it is also known that in a model animal of chronical damaged kidney, the expression of both TRPC3 and TRPC6 are enhanced, suggesting that both of these molecules could be rational therapeutic targets.
Here, we developed “L862”, a novel selective TRPC3/6 dual inhibitor. This compound has a superior pharmacokinetic property compared to previously reported compounds, which allows it to be administered orally. We investigated the effect of L862 in normal rats and puromycin aminonucleoside (PAN)-induced rat nephrotic model. This compound exerted significant improvement of proteinuria, while no apparent toxicities were observed in normal rats. These results suggest that L862 would be a promising therapeutic compound for nephrotic syndrome, as well as other TRPC3/6-related diseases.