Frontiers in pharmacology · 2026
Bruceine A attenuates renal tubulointerstitial fibrosis by inhibiting the Wnt7a/PI3K/AKT pathway.
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Li Shuangyu, Wang Renqing, Wang Tong, Zhang Wenyan, Xu Shengchun, Ren Zhenhua, Luo Renfei
Аннотация
INTRODUCTION: Tubulointerstitial fibrosis (TIF) is a major pathological feature of progressive chronic kidney disease (CKD), yet effective pharmacological therapies remain limited. Bruceine A (BA), a quassinoid isolated from Brucea javanica, has been reported to exert renoprotective effects in glomerular diseases. However, its pharmacological role in renal TIF and the underlying mechanisms remain poorly defined.
METHODS: In this study, we investigated the effects of BA in two classic animal models of TIF, unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI), as well as in TGF-β1-stimulated HK-2 cells.
RESULTS: BA significantly attenuated renal histopathological injury, inflammatory responses, and fibrotic changes in both in vivo models, and improved renal function in UIRI mice. BA dose-dependently suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibrotic responses in HK-2 cells. Mechanistically, RNA sequencing identified Wnt7a as a BA-responsive gene in fibrotic kidneys. BA consistently reduced Wnt7a expression in vivo and in vitro, while integrated RNA-seq and network pharmacology analyses implicated PI3K/AKT signaling as a key downstream pathway, which was further supported by reduced PI3K and AKT phosphorylation after BA treatment. Moreover, recombinant Wnt7a protein and the AKT agonist SC79 partially reversed BA-mediated suppression of fibrotic marker expression in HK-2 cells. Recombinant Wnt7a also partially restored PI3K/AKT activation.
DISCUSSION: Collectively, these findings suggest that BA attenuates renal tubulointerstitial injury and fibrosis, potentially through modulation of the Wnt7a/PI3K/AKT signaling pathway, supporting its potential as a therapeutic candidate for TIF.
METHODS: In this study, we investigated the effects of BA in two classic animal models of TIF, unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI), as well as in TGF-β1-stimulated HK-2 cells.
RESULTS: BA significantly attenuated renal histopathological injury, inflammatory responses, and fibrotic changes in both in vivo models, and improved renal function in UIRI mice. BA dose-dependently suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibrotic responses in HK-2 cells. Mechanistically, RNA sequencing identified Wnt7a as a BA-responsive gene in fibrotic kidneys. BA consistently reduced Wnt7a expression in vivo and in vitro, while integrated RNA-seq and network pharmacology analyses implicated PI3K/AKT signaling as a key downstream pathway, which was further supported by reduced PI3K and AKT phosphorylation after BA treatment. Moreover, recombinant Wnt7a protein and the AKT agonist SC79 partially reversed BA-mediated suppression of fibrotic marker expression in HK-2 cells. Recombinant Wnt7a also partially restored PI3K/AKT activation.
DISCUSSION: Collectively, these findings suggest that BA attenuates renal tubulointerstitial injury and fibrosis, potentially through modulation of the Wnt7a/PI3K/AKT signaling pathway, supporting its potential as a therapeutic candidate for TIF.