TRIM32 Inhibition Attenuates Apoptosis, Oxidative Stress, and Inflammatory Injury in Podocytes Induced by High Glucose by Modulating the Akt/GSK-3β/Nrf2 Pathway.

Abstract

Hyperglycemia-induced oxidative stress in podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported to be a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. This work aimed to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress, and inflammatory response in podocytes in vitro. Our results showed a marked increase in TRIM32 expression in HG-exposed podocytes and the glomeruli of diabetic mice. Loss-of-function experiments showed that TRIM32 knockdown improves the viability of HG-stimulated podocytes and suppresses HG-induced apoptosis, oxidative stress, and inflammatory responses in podocytes. Further investigation revealed that TRIM32 inhibition enhances the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which is associated with the modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, Akt suppression abrogated the TRIM32 knockdown-mediated activation of Nrf2 in HG-exposed podocytes. Nrf2 knockdown also markedly abolished the protective effects induced by TRIM32 inhibition o in HG-exposed podocytes. In summary, this work demonstrated that TRIM32 inhibition protects podocytes from HG-induced injury by potentiating Nrf2 signaling through modulation of Akt/GSK-3β signaling. The findings reveal the potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.