REDD1-dependent GSK3β signaling in podocytes promotes canonical NF-κB activation in diabetic nephropathy

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Diabetes mellitus is linked to progressive kidney disease, characterized by an enhanced immune response.
• The stress response protein regulated in development and DNA damage response 1 (REDD1) is implicated in diabetic kidney complications.
• REDD1's role in activating the pro-inflammatory transcription factor NF-κB in diabetic nephropathy requires further elucidation.

Purpose of the Study:

• To delineate the specific signaling pathways through which REDD1 drives NF-κB activation in diabetic nephropathy.
• To investigate the role of glycogen synthase kinase 3β (GSK3β) in REDD1-mediated inflammation in kidney cells.

Main Methods:

• Utilized streptozotocin (STZ)-induced diabetes in mice and hyperglycemic conditions in human podocyte cultures.
• Assessed the activity of GSK3β, NF-κB, and the IκB kinase (IKK) complex.
• Investigated the impact of REDD1 ablation, GSK3β suppression, and GSK3 inhibitors on inflammatory markers and immune cell infiltration.

Main Results:

• STZ-induced diabetes increased kidney GSK3β activity, a process dependent on REDD1.
• REDD1 enhanced GSK3β activity in hyperglycemic podocytes; GSK3β suppression normalized NF-κB activation and pro-inflammatory factors.
• REDD1-dependent GSK3β signaling activated the IKK complex, leading to NF-κB activation and increased macrophage chemotaxis and kidney immune cell infiltration.

Conclusions:

• Hyperglycemia amplifies GSK3β activation in a REDD1-dependent manner, initiating canonical NF-κB signaling.
• This pathway contributes to an augmented renal immune response in diabetic nephropathy.
• Targeting the REDD1-GSK3β-NF-κB axis may offer therapeutic strategies for diabetic kidney disease.