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

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

  • Int Immunopharmacol. 2024 Mar 12:131:111785. doi: 10.1016/j.intimp.2024.111785.
Zhen-Wang Zhang 1,  Ming-Qiu Tang 2,  Wu Liu 1,  Yi Song 2,  Man-Jun Gao 2,  Ping Ni 3,  Dan-Dan Zhang 4,  Qi-Gui Mo 5,  Bao-Qing Zhao 6
Affiliations

Affiliations

  • 1 Medicine Research Institute & Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437000, PR China.
  • 2 Schools of Pharmacy, Hubei University of Science and Technology, Xianning 437000, PR China.
  • 3 Clinical Medicine, Hubei University of Science and Technology, Xianning 437000, PR China.
  • 4 Medicine Research Institute & Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437000, PR China. Electronic address: [email protected].
  • 5 Medicine Research Institute & Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437000, PR China. Electronic address: [email protected].
  • 6 Medicine Research Institute & Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437000, PR China. Electronic address: [email protected].
PMID: 38479158 DOI: 10.1016/j.intimp.2024.111785
Abstract

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-1β 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.

Keywords

Dapagliflozin; Diabetes mellitus; HO-1; Pyroptosis; miR-155-5p.

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  • HY-P1009
    ≥98.0%, Caspase 1/4 Inhibitor