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Background <p>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.</p> Methods <p>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&#xa0;g/kg/d for 12&#xa0;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.</p> Results <p>M-SYFSF treatment significantly improved renal function parameters, reducing serum creatinine (<i>p</i> &lt; 0.001) and proteinuria (<i>p</i> &lt; 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 <i>p</i> &lt; 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 (<i>p</i> &lt; 0.001), while enhancing antioxidant enzyme activities.</p> Conclusions <p>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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年1月9日

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  • Bingnan Di,
  • Yaotan Li,
  • Jinyan Wei,
  • Yizhen Han,
  • Jinyi Hou,
  • Xinghua Zhang,
  • Xiaochang Wu,
  • Weijing Liu,
  • Huijuan Zheng,
  • Yaoxian Wang

摘要

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.