P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy.

Area of Science:

• Nephrology
• Molecular Biology
• Diabetology

Background:

• Diabetic nephropathy is a major cause of end-stage renal disease globally.
• Increased urinary Adenosine triphosphate (ATP) is observed in diabetic conditions.
• Purinergic receptors play a role in renal pathophysiology.

Purpose of the Study:

• To investigate the role of purinergic receptors, specifically P2X7R, in diabetic nephropathy.
• To elucidate the mechanism by which P2X7R affects podocyte autophagy and damage in diabetes.
• To explore P2X7R as a potential therapeutic target for diabetic nephropathy.

Main Methods:

• Examined purinergic receptor expression in the renal cortex of wild-type and P2X7R knockout diabetic mice.
• Assessed podocyte marker (podocin) and autophagy marker (LC-3II) expression.
• Utilized in vitro podocyte culture exposed to high glucose, P2X7R siRNA, and pathway inhibitors (Akt, mTOR).

Main Results:

• P2X7R expression was significantly increased in the renal cortex of diabetic mice and co-localized with podocytes.
• P2X7R deficiency preserved podocin expression and normalized LC-3II levels in diabetic kidneys.
• High glucose reduced podocyte autophagy (decreased LC-3II, increased p62) via Akt-mTOR activation; P2X7R inhibition/knockdown restored autophagy.

Conclusions:

• Increased P2X7R in diabetic podocytes contributes to autophagy inhibition through the Akt-mTOR pathway.
• This P2X7R-mediated autophagy suppression exacerbates podocyte damage, promoting diabetic nephropathy.
• Targeting P2X7R presents a promising therapeutic strategy for managing diabetic nephropathy.