Gq signaling causes glomerular injury by activating TRPC6

Area of Science:

• Nephrology
• Molecular Biology
• Genetics

Background:

• Gain-of-function mutations in Transient Receptor Potential Channel C6 (TRPC6) are linked to familial focal segmental glomerulosclerosis (FSGS).
• Gq signaling pathways activate TRPC6, suggesting their role in glomerular diseases.

Purpose of the Study:

• To investigate the role of constitutively active Gq signaling in podocytes in the development of FSGS.
• To examine the effects of Gq activation on TRPC6 expression and kidney injury.

Main Methods:

• Developed a murine model with podocyte-specific expression of a constitutively active Gq alpha subunit (GqQ>L).
• Administered puromycin aminonucleoside (PAN) to induce nephrosis.
• Assessed albuminuria, glomerular structure, podocyte number, and TRPC6 expression.
• Investigated the effects of TRPC6 deletion and calcineurin inhibition (FK506).
• Examined GqQ>L effects in a diabetic kidney disease model.

Main Results:

• GqQ>L expression in podocytes led to albuminuria, FSGS features, and podocyte loss.
• Gq activation increased calcineurin activity and TRPC6 upregulation in kidneys.
• TRPC6 deletion prevented FSGS and protected against PAN-induced kidney injury.
• FK506 partially ameliorated proteinuria and tubular injury but had limited effects on glomerular pathology.
• GqQ>L exacerbated kidney injury in a diabetic mouse model.

Conclusions:

• Constitutive Gq activation in podocytes drives FSGS development, partly via calcineurin-dependent TRPC6 upregulation.
• Targeting the Gq/TRPC6 signaling pathway holds potential for treating glomerular diseases, including diabetic kidney disease.