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Published on: November 7, 2017
Gain-of-function, focal segmental glomerulosclerosis Trpc6 mutation minimally affects susceptibility to renal injury
Brittney J Brown1, Kimber L Boekell1, Brian R Stotter1,2
1Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Abstract:
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 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 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.
Insights
Gain-of-function mutations in TRPC6 channels cause focal segmental glomerulosclerosis (FSGS). This study found that a specific TRPC6 gain-of-function mutation in mice confers only mild susceptibility to glomerular injury, challenging previous assumptions.
Area of Science:
- Nephrology
- Molecular biology
- Genetics
Background:
- Mutations in TRPC6 channels are linked to autosomal dominant focal segmental glomerulosclerosis (FSGS) in humans.
- Many TRPC6 mutations exhibit gain-of-function effects on cation channel activity, impacting cellular signaling.
- Previous in vivo studies primarily used TRPC6-deficient models, limiting understanding of gain-of-function mutation effects.
Purpose of the Study:
- To investigate the in vivo effects of a gain-of-function TRPC6 mutation (E896K) associated with FSGS.
- To characterize the renal phenotype of mice engineered to carry the Trpc6 E896K gain-of-function mutation.
- To compare the Trpc6 E896K mutant phenotype with wild-type and Trpc6-deficient models.
Main Methods:
- Development of mice with a targeted gain-of-function Trpc6 mutation (E896K).
- Assessment of renal pathology, albuminuria, and susceptibility to nephrotoxic models (PAN nephrosis, albumin overload, angiotensin II infusion, folate injury).
- Evaluation of TRPC6 protein expression and function in glomeruli.
Main Results:
- Homozygous Trpc6 E896K mice showed minimal renal pathology and late-onset albuminuria.
- The mutation did not increase susceptibility to PAN nephrosis but caused a slight delay in recovery from albumin overload.
- Chronic angiotensin II infusion led to transiently increased albuminuria and a non-significant trend toward glomerular injury, contrasting with Trpc6-deficient phenotypes.
- No significant interstitial fibrosis was observed in response to various injury models.
- TRPC6 protein and agonist-induced calcium influx were undetectable in glomeruli.
Conclusions:
- A gain-of-function TRPC6 mutation confers only mild susceptibility to glomerular injury in mice.
- The in vivo phenotype of this gain-of-function mutation is largely opposite to that of TRPC6 deficiency.
- These findings highlight the complex role of TRPC6 in glomerular disease pathogenesis.
