Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Gain-of-function mutations in TRPC6 cause focal segmental glomerulosclerosis.
• TRPC6 expression is elevated in human glomerular diseases like membranous nephropathy.
• TRPC6 overactivation was hypothesized to be detrimental to podocytes via calcium signaling.

Purpose of the Study:

• To investigate the context-dependent role of TRPC6 in podocyte function.
• To determine the mechanism by which TRPC6 affects podocyte injury.
• To explore the clinical relevance of TRPC6 and CaMKII in human kidney disease.

Main Methods:

• Overexpression and genetic/pharmacological inactivation of TRPC6 in podocytes.
• Complement-mediated injury assays.
• Analysis of TRPC6 transgenic and null mice in a nephrotoxic serum nephritis model.
• Immunohistochemical analysis of human membranous nephropathy biopsies.

Main Results:

• TRPC6 overexpression alone did not alter podocyte morphology.
• TRPC6 overexpression protected podocytes from complement-mediated injury.
• TRPC6 inactivation increased podocyte susceptibility to complement.
• TRPC6's protective effect was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation.
• TRPC6 transgenic mice showed reduced proteinuria and foot process effacement, while TRPC6 null mice showed increased proteinuria.
• Active CaMKII in human membranous nephropathy podocytes correlated with TRPC6 expression.

Conclusions:

• TRPC6 plays a dual role in podocytes: acute activation protects against complement-mediated damage.
• Chronic TRPC6 overactivation contributes to focal segmental glomerulosclerosis.
• TRPC6-CaMKII signaling is a critical pathway in podocyte injury and protection.