Ginaton injection alleviates cisplatin-induced renal interstitial fibrosis in rats via inhibition of apoptosis through regulation of the p38MAPK/TGF-β1 and p38MAPK/HIF-1α pathways.

Abstract

Ginaton injection (Ginkgo biloba extract; GBE) has been reported to protect against cisplatin-induced acute renal failure in rats. In the present study, the effects and molecular mechanisms of GBE on cisplatin-induced renal interstitial fibrosis were evaluated using a rat model. The rats were intraperitoneally injected with cisplatin once on the first day and a subset of rats were treated with GBE or SB203580 (SB; a specific p38 MAPK inhibitor) daily from days 22 to 40. The levels of N-acetyl-β-D-Glucosaminidase (NAG) in the urine, and of urea nitrogen (BUN) and creatinine (Scr) in the blood were assessed. The damage and fibrosis of renal tissues were evaluated using hematoxylin and eosin staining, as well as Masson's trichrome staining, respectively. Apoptosis in renal tissues was detected using a TUNEL assay. The protein expression levels of α-smooth muscle actin (SMA), collagen 1 (Col I), Bax, Bcl-2, caspase-3/cleaved caspase-3, hypoxia-inducible factor-1α (HIF-1α), TGF-β1 and p38MAPK, as well as the mRNA levels of p38MAPK in renal tissues were investigated. The results showed that GBE markedly reduced the levels of urinary NAG, Scr and BUN, and renal expression of α-SMA and Col I levels were also reduced. Furthermore, GBE significantly reduced renal tissue injury and the relative area of renal interstitial fibrosis induced by cisplatin. GBE effectively reduced the apoptotic rate of renal tissues, the protein expression levels of Bax, cleaved caspase-3, phospho-p38MAPK, TGF-β1 and HIF-1α, as well as the mRNA expression levels of p38MAPK in renal tissues induced by cisplatin, whereas GBE significantly increased Bcl-2 protein expression. SB exhibited similar effects to GBE, although it was not as effective. In summary, the present study is the first to show that GBE significantly alleviated renal interstitial fibrosis following cisplatin-induced acute renal injury. The mechanisms by which GBE exhibited its effects were associated with the inhibition of apoptosis via downregulation of the p38MAPK/TGF-β1 and p38MAPK/HIF-1α signaling pathways.