Synaptopodin Limits TRPC6 Podocyte Surface Expression and Attenuates Proteinuria.

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Gain-of-function mutations in TRPC6 are linked to familial FSGS.
• Increased wild-type TRPC6 expression occurs in acquired proteinuric diseases.
• Synaptopodin is crucial for podocyte function and downregulated in glomerular diseases.

Purpose of the Study:

• To investigate if synaptopodin regulates TRPC6 surface expression and activity.
• To elucidate the mechanism of synaptopodin-TRPC6 interaction.
• To explore therapeutic potential for proteinuric diseases.

Main Methods:

• Investigated synaptopodin-TRPC6 interaction in cultured mouse podocytes.
• Utilized synaptopodin knockdown and overexpression models.
• Examined TRPC6 surface expression, calcium influx, and apoptosis.
• Assessed effects of cyclosporin A in LPS-induced proteinuria mouse models (wild-type and TRPC6 knockout).

Main Results:

• Synaptopodin and TRPC6 show indirect interaction in podocytes.
• Synaptopodin knockdown increased, while overexpression decreased, TRPC6 surface expression.
• Synaptopodin-dependent TRPC6 regulation requires intact actin and microtubule cytoskeletons.
• TRPC6 overexpression in synaptopodin-depleted podocytes enhanced calcium influx and induced apoptosis.
• Cyclosporin A reduced proteinuria and reversed increased TRPC6 surface expression in vivo.

Conclusions:

• Altered synaptopodin levels affect TRPC6 localization and activity, contributing to podocyte dysfunction.
• TRPC6 surface expression is modulated by synaptopodin via cytoskeletal mechanisms.
• Reducing TRPC6 surface levels represents a potential therapeutic strategy for proteinuric kidney diseases.