larixol and Glomerulosclerosis--Focal-Segmental

Gain of function mutations in TRPC6 channels can cause autosomal dominant forms of focal segmental glomerulosclerosis (FSGS). Validated inhibitors of TRPC6 channels that are biologically active on FSGS-related TRPC6 mutants are eagerly sought.. We synthesized new TRPC6-inhibiting modulators from larixol, a resiniferous constituent of Larix decidua, and tested the potency and selectivity in cell lines stably expressing various TRPC channel isoforms. Channel activation was followed by Ca. LC exhibited an about 30-fold preference for TRPC6 over TRPC3 channels and a fivefold preference for TRPC6 over TRPC7 channels. Six FSGS-related TRPC6 mutants, including the highly active M132T and R175Q variants, were strongly inhibited by 1 μM LC. Surprisingly, no TRPC6-related Ca. In spite of their low abundance in native podocytes, native TRPC6 channels are targetable using larixol-derived TRPC6 inhibitors. As observed with wild-type TRPC6 channels, FSGS-related TRPC6 mutants were sensitive to the newly developed inhibitors, paving the way for experimental therapies.

Topics: Animals; Calcium Signaling; Cell Survival; Cells, Cultured; Diterpenes; Glomerulosclerosis, Focal Segmental; HEK293 Cells; Humans; Kidney Glomerulus; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Myocytes, Smooth Muscle; Podocytes; Pulmonary Artery; Rats, Wistar; TRPC6 Cation Channel