Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury in several mouse models

Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury in several mouse models

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Mutations in TRPC6 are a cause of autosomal dominant focal segmental glomerulosclerosis in humans.Many of these mutations are known to have a gain-of-function effect on the non-specific cation channel function of TRPC6.In vitro studies have suggested these mutations affect several signaling pathways, but in vivo studies have largely compared wild-type and Trpc6-deficient rodents.

We developed mice carrying a gain-of-function Trpc6 mutation encoding an E896K amino acid change, corresponding to a known FSGS mutation in TRPC6.Homozygous mutant Trpc6 animals have no appreciable renal pathology, and do not develop albuminuria until very advanced age.The Trpc6E896K mutation does a not impart susceptibility to PAN nephrosis.

The animals show a slight delay in recovery from the albumin overload model.In response to chronic angiotensin II infusion, Trpc6E896K/E896K mice have slightly greater albuminuria initially compared to wild-type animals, an effect that is lost at later time points, and a statistically non-significant trend toward more glomerular injury.This phenotype is nearly opposite Accessories to that of Trpc6-deficient animals previously described.

The Trpc6 mutation does not appreciably impact renal interstitial fibrosis in response to either angiotensin II infusion, or folate-induced kidney injury.TRPC6 protein and TRPC6-agonist induced calcium influx could not be detected in glomeruli.In sum, these findings suggest that a gain-of-function Trpc6 mutation confers only a mild susceptibility to glomerular injury in the mouse.