Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing...

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Diabetic kidney disease (DKD) is characterized by impaired podocyte autophagy, a key process for cell protection.
• The unique regulation of podocyte autophagy, independent of mTOR and AMPK pathways, leaves its mechanisms in DKD unclear.

Purpose of the Study:

• To elucidate the role of the calcium channel TRPC6 and cysteine protease calpains in podocyte autophagy dysfunction in DKD.
• To investigate TRPC6 and calpain as potential therapeutic targets for DKD.

Main Methods:

• Investigated the impact of TRPC6 and calpains on podocyte autophagy in mouse models of DKD.
• Utilized streptozotocin-induced and BTBR ob/ob mouse models for in vivo studies.
• Assessed autophagic flux, podocyte injury markers (nephrin), and albuminuria.

Main Results:

• Diabetes increased TRPC6 expression and impaired podocyte autophagic flux in mice.
• TRPC6 knockdown enhanced autophagic flux by reducing calpain activity.
• Calpain inhibition or calpastatin overexpression normalized autophagy, reduced nephrin loss, and prevented albuminuria.
• Human kidney biopsies showed correlation between TRPC6, reduced calpastatin, autophagy blockade, and podocyte injury.

Conclusions:

• Identified a novel mechanism linking TRPC6 and calpain activity to impaired podocyte autophagy in DKD.
• Restoring podocyte autophagy by targeting TRPC6 and/or calpains presents a promising therapeutic strategy for DKD.