# Mechanism Analysis of Zuogui and Yougui Pills on Diabetic Nephropathy Through Transcriptional Regulatory Networks of HIF1A and PPARA

## TL;DR

This study explores how two traditional Chinese medicines, Zuogui and Yougui Pills, may help treat diabetic kidney disease by regulating key genes and proteins.

## Contribution

The study identifies shared and distinct mechanisms of ZGP and YGP in diabetic nephropathy through HIF1A and PPARA transcriptional networks.

## Key findings

- ZGP and YGP inhibit renal fibrosis by suppressing FN1 and MMP9 gene expression.
- HIF1A and PPARA are key transcription factors regulated by both pills, with downstream targets CA9, PDK1, and PDK4.
- Verbascoside and other compounds were identified as potential mediators or agonists of HIF1A and PPARA.

## Abstract

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 FN1 and MMP9 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. CA9 and PDK1, the downstream genes of HIF1A, and PDK4, 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.

The shared mechanisms of Zuogui Pill (ZGP) and Yougui Pill (YGP) for treating diabetic nephropathy is HIF1A‐CA9‐PDK1 and PPARA‐PDK4. ZGP and YGP inhibited renal fibrosis and relieved the decrease in glucose consumption through transcriptional regulatory network of HIF1A and PPARA. The active ingredients of ZGP and YGP were discovered for regulating HIF1A and PPARA.