Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Dapagliflozin alleviates renal podocyte pyroptosis via regulation of the HO­1/NLRP3 axis.

Diabetic nephropathy is one of the most significant complications of diabetes, resulting in increased patient mortality. Dapagliflozin is an inhibitor of sodium­glucose cotransporter 2 that has an important protective effect on the kidney. Recent studies showed that pyroptosis is involved in the advancement of diabetic nephropathy (DN). However, the potential molecular mechanisms underlying the association between pyroptosis and renal podocyte injury in DN remain unclear. Thus, the present study investigated the anti­pyroptotic function of dapagliflozin in podocytes and further clarified the potential mechanisms. In this study, a model of lipid metabolism disturbance was established through palmitic acid (PA) induction in a mouse podocyte clone 5 (MPC5) cell line. MPC5 PA­induced pyroptosis was measured by ELISA, western blotting, quantitative PCR and Hoechst 33342/propidium iodide double­fluorescence staining. The protective role of HO­1 was measured using knockdown and overexpression experiments. It was found that dapagliflozin attenuated the expression of pyroptosis­related proteins, including nucleotide oligomerization domain­like receptor thermal protein domain associated protein 3, apoptosis­associated speck­like protein containing a caspase activation and recruitment domain, caspase­1, IL­18 and IL­1ß in the PA group. Meanwhile, the heme oxygenase 1 (HO­1) expression level decreased within PA, an effect that was reversed by dapagliflozin. Furthermore, the expression of pyroptosis­related proteins and inflammatory cytokines was reduced following HO­1 overexpression. Therefore, these results suggested that dapagliflozin ameliorates MPC5 pyroptosis by mediating HO­1, which has a protective effect on diabetic nephropathy.