Modified Shen-Yan-Fang-Shuai formula attenuates diabetic kidney disease progression via regulation of HIF-1α-mediated mitochondrial energy metabolism.

BACKGROUND

Diabetic kidney disease (DKD) represents a major global health burden, affecting 20-40% of diabetic patients worldwide. Metabolic reprogramming mediated by hypoxia-inducible factor-1α (HIF-1α) plays a central role in DKD pathogenesis, yet effective therapeutic strategies remain limited. The Modified Shen-Yan-Fang-Shuai formula (M-SYFSF), a traditional Chinese medicine formulation, has demonstrated clinical efficacy in DKD treatment, but its underlying mechanisms remain unclear.

METHODS

A DKD model was established using streptozotocin-induced diabetic rats following unilateral nephrectomy. Thirty rats were randomly divided into sham operation, model, and M-SYFSF treatment groups (n = 10/group). M-SYFSF was administered at 11.34 g/kg/d for 12 weeks. Renal function, histopathology, oxidative stress markers, and metabolic parameters were assessed. Human proximal tubular epithelial cells (HK-2) were treated with advanced glycation end products under hypoxic conditions to establish an in vitro DKD model. HIF-1α overexpression and knockdown experiments were performed to investigate molecular mechanisms. Key glycolytic enzymes, mitochondrial dynamics proteins, and bioenergetic parameters were analyzed using Western blot, immunohistochemistry, immunofluorescence, and metabolic assays.

RESULTS

M-SYFSF treatment significantly improved renal function parameters, reducing serum creatinine (p < 0.001) and proteinuria (p < 0.001) while ameliorating characteristic DKD histopathological changes. M-SYFSF effectively suppressed HIF-1α expression and nuclear translocation, accompanied by consistent downregulation of key glycolytic enzymes including hexokinase 2, lactate dehydrogenase, and pyruvate dehydrogenase kinase 1. Metabolic analysis revealed that M-SYFSF promoted a shift from glycolysis toward oxidative phosphorylation, restoring mitochondrial ATP production capacity. Transmission electron microscopy demonstrated that M-SYFSF preserved mitochondrial ultrastructure and improved mitochondrial respiratory chain complex activities (I, III, and IV; all p < 0.01). M-SYFSF treatment enhanced mitochondrial fusion by upregulating Mfn1 and Mfn2 while suppressing fission proteins Drp1 and Fis1. HIF-1α overexpression experiments confirmed that M-SYFSF's metabolic and mitochondrial protective effects were mediated through HIF-1α pathway modulation. Additionally, M-SYFSF significantly reduced oxidative stress markers, including 8-OHdG and malondialdehyde levels (p < 0.001), while enhancing antioxidant enzyme activities.

CONCLUSIONS

M-SYFSF exerts significant nephroprotective effects in diabetic kidney disease by targeting HIF-1α-mediated metabolic reprogramming. The therapeutic mechanisms involve suppression of pathological glycolytic metabolism, restoration of mitochondrial function and dynamics, and enhancement of antioxidant capacity. These findings provide mechanistic validation for M-SYFSF as a promising multi-target therapeutic approach for diabetic kidney disease management and establish HIF-1α as a key therapeutic target for metabolic intervention in DKD treatment.