The extremely complex, multivariate, and systemic pathophysiology of diabetic nephropathy is brought on by prolonged exposure to hyperglycemia, making the quest for the best therapeutic approach crucial and urgent. Accumulating evidence suggests that pyroptosis and inflammation contribute to the development of diabetic nephropathy. Zinc fingers and homeoboxes 2 (ZHX2) were recently discovered to be a new regulator of inflammatory response. However, the role and potential molecular mechanisms of ZHX2 in diabetic nephropathy remain unclear. Exosomes derived from gingival mesenchymal stem cells (GMSCs-Exo) were successfully isolated and characterized. GMSCs-Exo reversed high glucose-induced podocyte pyroptosis and inflammation. ZHX2 was highly expressed in GMSCs-Exo. Furthermore, ZHX2 derived from GMSCs-Exo reversed podocyte pyroptosis and inflammation induced by HG. Additionally, ZHX2 was enriched in the FABP4 promoter region and transcriptionally inhibited the mRNA and protein levels of FABP4. GMSCs-Exo-derived ZHX2 abolished HG-induced podocyte pyroptosis and inflammation by inhibiting FABP4 and blocking the advanced glycation endproducts/the receptor of advanced glycation endproducts/NOD-like receptor family pyrin domain-containing 3 (AGEs/RAGE/NLRP3) pathway. Similarly, GMSCs-Exo-derived ZHX2 alleviated renal injury, pyroptosis, and inflammation in diabetic nephropathy mice. In conclusion, our findings demonstrated that ZHX2 protects against diabetic nephropathy by binding to the FABP4 promoter and reducing the expression of FABP4. We also showed that GMSCs-Exo-derived ZHX2 reversed HG-induced podocyte pyroptosis and inflammation by inhibiting the AGEs/RAGE/NLRP3 pathway. ZHX2 derived from GMSCs-Exo also alleviated tubular injury, pyroptosis, and inflammation in diabetic nephropathy mice. The therapeutic potential of targeting ZHX2 to treat diabetic nephropathy is clarified by these findings.
Wang et al. (Wed,) studied this question.