Mechanism Analysis of Zuogui and Yougui Pills on Diabetic Nephropathy Through Transcriptional Regulatory Networks of <scp>HIF1A</scp> and <scp>PPARA</scp>

Diabetic nephropathy, a serious diabetes complication, lacks effective treatments. Traditional Chinese medicine Zuogui Pill (ZGP) and Yougui Pill (YGP) have a definite clinical adjunctive effect on diabetic nephropathy. Given their similar compositions, studying their shared mechanisms could provide novel perspectives into discovering therapeutic targets for diabetic nephropathy. Extraction of ZGP (EZP) and YGP (EYP) was prepared by in vitro digestion. EZP and EYP inhibited the gene expression of <i>FN1</i> and <i>MMP9</i> in a renal fibrosis cell model. A transcriptional regulatory network revealed EZP and EYP have similar mechanisms, with HIF1A as a key transcription factor. In an insulin resistance cell model, EZP and EYP led to the decrease in glucose consumption. A transcriptional regulatory network suggested that EZP and EYP have different regulatory panels, but PPARA was the common transcriptional factor. <i>CA9</i> and <i>PDK1</i>, the downstream genes of HIF1A, and <i>PDK4</i>, the downstream gene of PPARA, were activated by both EZP and EYP, which showed the potential new targets of diabetic nephropathy. A total of 42 compounds from EZP and EYP were screened as the potential mediators of HIF1AN and EGLN1, interacted proteins and common targets of HIF1A. A total of 8 compounds, including verbascoside, were screened as the potential PPARA agonists based on molecular docking. Verbascoside improved the decrease in glucose consumption. The study clarified the mechanism of the ZGP and YGP by regulating the transcriptional regulatory network of HIF1A and PPARA and provided new ideas for the discovery of potential targets for the treatment of diabetic nephropathy and the development of natural nutrients.