Syringaresinol attenuates kidney injury by inhibition of pyroptosis via activating the Nrf2 antioxidant pathway in diabetic nephropathy

Abstract

Background and Purpose: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes that has limited treatment options. NLRP3-initiated pyroptosis is tightly implicated in DN progression. Mitochondrial ROS (mtROS) are a critical trigger of NLRP3 activation. Syringaresinol, a natural plant-derived polyphenolic compound, possesses strong antioxidant properties. However, whether syringaresinol provides renoprotection in DN remains unclear. Experimental Approach: The renoprotection effects of syringaresinol were investigated in streptozotocin-induced wild-type and Nrf2-KO mice. The underlying mechanism of syringaresinol on DN was assessed in diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as glomerular mesangial cells HBZY-1. Key Results: Syringaresinol treatment ameliorated renal structural and functional changes in streptozotocin-induced diabetic mice, including renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, podocyte foot process effacement and albuminuria. Mechanistically, syringaresinol prevented the NLRP3/Caspase-1/GSDMD pyroptosis pathway and promoted Nrf2 expression and nuclear transfer in both diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as HBZY-1 cells. After that, the nuclear-transferred Nrf2 upregulated the antioxidant genes HO-1 and MnSOD, thereby effectively improving mitochondrial dysfunction and decreasing excess cytosolic ROS and mtROS. Most importantly, knockout of Nrf2 abolished the syringaresinol-mediated renoprotection and antioxidant effects and subsequent mtROS overproduction, resulting in the activation of NLRP3/Caspase-1/GSDMD signaling. Conclusion and Implications: Syringaresinol attenuated diabetic renal lesions by preventing the NLRP3/Caspase-1/GSDMD pyroptosis pathway in an Nrf2-dependent manner. This suggests that syringaresinol may represent promising therapeutic options for DN.

A Review of Medicinal Plants with Renoprotective Activity in Diabetic Nephropathy Animal Models

“…Its ameliorating activity for the progression of DN is observed in diabetic rats and occurs through the activation of Nrf2 and the inactivation of TGF-β1/Smad pathways [ 71 ]. In diabetic C57BL/6 mice, syringaresinol inhibits pyroptosis by activating the Nrf2 antioxidant pathway [ 72 ].…”