Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. May 15, 2025; 16(5): 102196
Published online May 15, 2025. doi: 10.4239/wjd.v16.i5.102196
Shenfushu granules attenuate diabetic kidney disease by inhibiting PIK3R1/protein kinase B/heparanase-mediated endothelial-mesenchymal transition
Xi-Ding Yang, Si-Jia Ma, Da-Xiong Xiang, Yong-Yu Yang
Xi-Ding Yang, Si-Jia Ma, Da-Xiong Xiang, Yong-Yu Yang, Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
Author contributions: Yang XD contributed to writing original draft, methodology, investigation; Ma SJ contributed to writing, review and editing; Xiang DX contributed to data curation, funding acquisition, conceptualization; Yang YY contributed to data curation, writing, review and editing, funding acquisition, conceptualization.
Supported by the Changsha Science and Technology Major Project, No. kh2205035; the Hunan Traditional Chinese Medicine Science and Technology Project, No. 2021061; and the Natural Science Foundation of Hunan Province, No. 2025JJ80080.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: This animal study was reviewed and approved by The Second Xiangya Hospital of Central South University’s Animal Ethics and Welfare Committee (No. 2021558).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yong-Yu Yang, MD, Associate Professor, Department of Pharmacy, The Second Xiangya Hospital of Central South University, No. 139 Renmin Middle Road, Furong District, Changsha 410011, Hunan Province, China. yongyuyang@csu.edu.cn
Received: October 14, 2024
Revised: February 9, 2025
Accepted: March 18, 2025
Published online: May 15, 2025
Processing time: 195 Days and 6.1 Hours
Abstract
BACKGROUND

Injury to the glomerular filtration barrier causes diabetic kidney disease (DKD), and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells. Shenfushu granules (SFSGs) can treat chronic renal failure; however, their role and mechanism in DKD remain unclear.

AIM

To investigate the role of SFSGs in delaying DKD progression and their underlying mechanism in a streptozotocin-induced DKD mouse model.

METHODS

The microalbumin content in the urine and the blood glucose, creatinine, and blood urea nitrogen levels in the serum were measured. The expression and distribution of α-smooth muscle actin (α-SMA), heparan sulfate (HS) and cluster of differentiation (CD) 31 were observed through immunofluorescence or immunohistochemistry. Western blotting was conducted to measure the expression of CD31, α-SMA, PIK3R1, protein kinase B (AKT), phospho-PIK3R1, phospho-AKT, and heparanase-1. Network pharmacology was conducted to screen and identify the core components and targets of SFSGs. Molecular docking and dynamic simulations were performed to evaluate the binding ability of the core components of SFSGs to their core targets.

RESULTS

Compared with those in the model group, the 24-hour microalbuminuria (188.2 ± 20.1 and 140.4 ± 24.7 vs 323.2 ± 44.4), serum creatinine (79.4 ± 2.6 and 68.7 ± 6.0 vs 110.2 ± 4.8), blood urea nitrogen (14.4 ± 1.1 and 13.1 ± 0.5 vs 19.5 ± 1.1), and renal index (20.3 ± 1.0 and 19.6 ± 0.8 vs 25.3 ± 1.7) were significantly lower in the SFSGs (2.08 and 4.16 g/kg/day extract)-treated DKD mice. SFSGs inhibited the downregulation of CD31 and the upregulation of α-SMA in the glomerular endothelial cells of DKD mice. Additionally, SFSGs suppressed the decrease in glycocalyx thickness and the expression of its component HS. Network pharmacology revealed that PIK3R1 was the core target of SFSGs. SFSGs markedly downregulate the expression of phospho-PIK3R1, phospho-AKT, and heparanase-1. However, the PIK3R1 agonist abolished the regulatory effect of SFSGs on the expression of CD31, α-SMA, and heparanase-1.

CONCLUSION

Collectively, these results suggest that SFSGs can significantly delay DKD progression and inhibit injury to the glycocalyx and the endothelial-mesenchymal transition of glomerular endothelial cells. This mechanism is related to PIK3R1/AKT/heparanase-1 signaling pathway regulation.

Keywords: Diabetic kidney disease; Glomerular filtration barrier; Glycocalyx; Shenfushu granules; PIK3R1; Heparanase-1; Endothelial-mesenchymal transition

Core Tip: Shenfushu granules (SFSGs) can delay the progression of diabetic kidney disease (DKD) by reducing the levels of serum creatinine, urea nitrogen, and urinary microalbumin in DKD mice and reducing damage to glomeruli. SFSGs reduce glomerular endothelial-mesenchymal transition, which is characterized by filtration barrier damage. SFSGs affect the endothelial-mesenchymal transition mediated by the PIK3R1/protein kinase B/heparanase-1 signaling pathway. The main active ingredient of SFSGs strongly binds with PIK3R1.