Exploring the mechanism of Shenhua tablet alleviating renal injury by regulating macrophage glycolysis hypoxia-inducible factor-1α/ pyruvate kinase M2 signaling pathway in diabetic kidney disease mice.

Abstract

Objective: To investigate the impact of Shenhua tablet (, SHT) on renal macrophage polarization and renal injury in mice with diabetic kidney disease (DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α (HIF-1α) and pyruvate kinase M2 (PKM2) signaling pathway, along with the glycolysis metabolism pathway.

Methods: The animals were divided into the following groups: Model, Control, dapagliflozin, SHT low-dose, SHT medium-dose, and SHT high-dose. We assessed 24-hour urine protein (24 h-UTP) levels, urinary albumin-to-creatinine ratio, and regularly monitored fasting blood glucose during the treatment period. After treatment, we examined renal tissue structure, renal function (urea nitrogen, uric acid, creatinine, cystatin C, β2-microglobulin), and glycolysis in renal macrophages. Additionally, we observed macrophage polarization in renal tissue and measured inflammatory factors (tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10, monocyte chemoattractant protein-1) to assess the immunoinflammatory status of the renal tissue. Finally, we investigated the expression of the HIF-1α/ PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.

Results: SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP, regulating blood glucose levels, improving renal tissue structure, protecting renal function, inhibiting macrophage glycolysis, reducing macrophage transformation to the M1 state, and suppressing the expression of the HIF-1α/PKM2 signaling pathway.

Conclusion: SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway. This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.