Shenfushu granules attenuate diabetic kidney disease by inhibiting /protein kinase B/heparanase-mediated endothelial-mesenchymal transition.

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, , protein kinase B (AKT), phospho-, 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 ± 24.7 323.2 ± 44.4), serum creatinine (79.4 ± 2.6 and 68.7 ± 6.0 110.2 ± 4.8), blood urea nitrogen (14.4 ± 1.1 and 13.1 ± 0.5 19.5 ± 1.1), and renal index (20.3 ± 1.0 and 19.6 ± 0.8 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 was the core target of SFSGs. SFSGs markedly downregulate the expression of phospho-, phospho-AKT, and heparanase-1. However, the 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 /AKT/heparanase-1 signaling pathway regulation.