Astragaloside IV Alleviates Podocyte Injury in Diabetic Nephropathy through Regulating IRE-1α/NF-κ B/NLRP3 Pathway

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Diabetic nephropathy (DN) is a major complication of diabetes, characterized by podocyte injury.
• Endoplasmic reticulum stress (ERS) and inflammation play critical roles in the pathogenesis of DN.
• Identifying therapeutic agents that target these pathways is crucial for managing DN.

Purpose of the Study:

• To investigate the protective effects of astragaloside IV (AS-IV) on podocyte injury in diabetic nephropathy (DN).
• To elucidate the underlying mechanism involving the inositol-requiring enzyme 1 alpha (IRE-1α)/nuclear factor kappa B (NF-κB)/NLR family pyrin domain containing 3 (NLRP3) signaling pathway.

Main Methods:

• In vitro: Podocytes were treated with high glucose (HG), AS-IV, or an IRE-1α inhibitor. Endoplasmic reticulum morphology, protein/mRNA expression (GRP78, IRE-1α, NF-κB, IL-1β, NLRP3, caspase-1, GSDMD-N, nephrin) were assessed.
• In vivo: A rat model of DN was established using streptozotocin (STZ). Rats were treated with AS-IV or an IRE-1α inhibitor. Blood glucose, kidney function markers, urinary protein, and renal pathology were evaluated. Gene and protein expression levels were measured.

Main Results:

• AS-IV treatment improved podocyte morphology and reduced endoplasmic reticulum swelling in vitro and alleviated renal pathological changes in vivo.
• AS-IV significantly decreased the expression of ERS markers (GRP78, IRE-1α) and inflammatory mediators (NF-κB, IL-1β, NLRP3, caspase-1, GSDMD-N) in both in vitro and in vivo models.
• AS-IV treatment increased nephrin expression and improved kidney function markers (blood glucose, BUN, SCr, urinary protein) in DN rats.

Conclusions:

• Astragaloside IV (AS-IV) exerts a podocyte-protective effect in diabetic nephropathy (DN).
• AS-IV mitigates podocyte injury by reducing endoplasmic reticulum stress (ERS) and inflammation.
• The protective mechanism involves the regulation of the IRE-1α/NF-κB/NLRP3 signaling pathway, improving podocyte pyroptosis.