Aloe-emodin ameliorates chronic kidney disease fibrosis by inhibiting PI3K-mediated signaling pathway.

Chronic kidney disease (CKD) impacts a vast number of individuals worldwide, culminating in renal fibrosis. Renal fibrosis serves as the main reason for end-stage renal failure. However, the current targeted treatment methods for renal fibrosis remain scarce. Aloe-emodin (AE) is a naturally occurring compound discovered in rhubarb and aloe. In this research, we investigated the underlying mechanisms of AE in adenine-induced mouse renal fibrosis models and TGFβ-1 stimulated renal tubular epithelial cells (HK-2). It was discovered that AE not only decelerated the decline of renal function in adenine-treated mice but also suppressed the expression of Collagen I and Fibronectin. Furthermore, network pharmacology analysis suggested that AE's treatment of renal fibrosis might function via the PI3K/Akt/GSK3β signaling pathway. In vivo and in vitro Western blot and immunofluorescence findings demonstrate that AE significantly resists the advancement of renal fibrosis by inhibiting α-smooth muscle actin (α-SMA) and vimentin. Simultaneously, findings from 740Y-P (a PI3K agonist) and siRNA (PI3K) indicate that AE inhibits the expression of the PI3K/Akt/GSK3β cascade by lowering PI3K's phosphorylation level. From a mechanistic perspective, through molecular docking and plasmid transfection, the specific base sequence of PI3K in HK-2 cells was altered for experimental validation. The outcomes illustrate that AE can directly bind with PI3K, inhibiting its activation, impeding the PI3K/Akt/GSK3β signal transmission, thereby ultimately suppressing renal fibrosis progression. In conclusion, PI3K/Akt/GSK3β is a potential therapeutic target for CKD-related renal fibrosis, making AE a promising new treatment alternative for this condition.