Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Src homology phosphotyrosyl phosphatase 2 (SHP-2) has been implicated in the pathogenesis of diabetic nephropathy (DN), while pyroptosis, an inflammatory form of programmed cell death, has also been associated with disease progression. However, the regulatory interplay between SHP-2 and pyroptosis in DN remains incompletely understood. In this study, we established DN rat models using a single intraperitoneal injection of streptozotocin (STZ) and HK-2 cells cultured under high-glucose (HG) conditions. Hematoxylin and eosin staining was performed to assess the histopathological changes in renal tissues, while immunofluorescence and Western blotting were used to evaluate SHP-2 and NLRP3 expression in both rat kidney tissues and HK-2 cells. Lentiviral transfection was performed to overexpress SHP-2 or NLRP3, following which the expression of pyroptosis-related proteins, activation of the NLRP3 inflammasome, and cell apoptosis were assessed by Western blot and flow cytometry. The results demonstrated that STZ-treated rats exhibited significant weight loss, hyperglycemia, and renal tissue injury. We observed an increase in SHP-2 expression in the kidney tissues of DN rats and in HK-2 cells exposed to high glucose, along with an elevated expression of NLRP3. SHP-2 knockdown suppressed NLRP3 inflammasome activation and mitigated HG-induced pyroptosis in renal tubular epithelial cells. Notably, overexpression of NLRP3 partially reversed the protective effects conferred by SHP-2 knockdown. These findings suggest that SHP-2 knockdown alleviates renal tubular epithelial cell injury in DN by inhibiting NLRP3 inflammasome-mediated pyroptosis.