Characterization of a Trpc6 Transgenic Mouse Associated with Early Onset FSGS

Area of Science:

• Nephrology
• Genetics
• Molecular Biology

Background:

• Mutations in the Transient Receptor Potential Channel 6 (TRPC6) gene are linked to autosomal dominant focal and segmental glomerulosclerosis (FSGS).
• Existing TRPC6 mouse models for FSGS have late onset and mild phenotypes, limiting their utility for drug testing.
• Calcium channels are potential therapeutic targets for FSGS, necessitating effective preclinical models.

Purpose of the Study:

• To develop a time-effective mouse model for studying TRPC6-associated FSGS.
• To emulate the M132T mutation found in a pediatric FSGS patient.
• To facilitate drug assessment and understand FSGS pathogenesis.

Main Methods:

• Generation of a novel transgenic mutant TRPC6 mouse model.
• Emulation of the specific M132T amino acid change associated with human FSGS.
• Analysis of phenotypic presentation and molecular consequences in the generated mice.

Main Results:

• The Trpc6 M131T mutant mice displayed early-onset proteinuria and FSGS.
• Overexpression of mutated TRPC6 in podocytes led to altered Axin2 and beta-catenin expression.
• Findings support a mechanism involving calcineurin-NFAT/Wnt signaling activation due to increased calcium influx.

Conclusions:

• The Trpc6 M131T mouse model exhibits early-onset FSGS-like phenotypes.
• This model is promising for studying TRPC6-mediated FSGS pathogenesis.
• It will aid in evaluating new therapeutic drugs and understanding disease pathways.