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  2. Ginkgo biloba leaf extract mitigates cisplatin-induced chronic renal interstitial fibrosis by inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells mediated by the Smad3/TGF-β1 and Smad3/p38 MAPK pathways

Ginkgo biloba leaf extract mitigates cisplatin-induced chronic renal interstitial fibrosis by inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells mediated by the Smad3/TGF-β1 and Smad3/p38 MAPK pathways

  • Chin Med. 2022 Feb 21;17(1):25. doi: 10.1186/s13020-022-00574-y.
Congying Wei  # 1 Yansong Zhang  # 1 Xiaobin Zhong 2 Sisi Lu 1 Xiaoqin Zou 1 Yufang Yang 3 Songqing Huang 1 Zhenguang Huang 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
  • 2 Regenerative Medicine Research Center of Guangxi Medical University, Shuangyong Road, Nanning, 530022, Guangxi Zhuang Autonomous Region, People's Republic of China. 1878125675@qq.com.
  • 3 Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China. 814896670@qq.com.
  • # Contributed equally.
Abstract

Background: Our previous study indicated that Ginkgo biloba leaf extract (EGb) could protect against cisplatin-induced acute kidney injury in rabbits. The present study aimed to determine the effects and potential molecular mechanisms of EGb on chronic renal interstitial fibrosis induced by cisplatin using in vivo and in vitro models.

Methods: Rats received a single dose of cisplatin on Day 1, and a subset of rats was intraperitoneally injected with EGb daily between Days 22-40. In vitro, HK-2 cells were treated with cisplatin, and a subset of cells was cultivated with EGb or SIS3 (SMAD3 inhibitor) for 48 h. Renal function of rats was assessed by detecting the levels of serum creatinine (Scr), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG). Hematoxylin and eosin staining and Masson's trichrome staining were used to evaluate the damage and fibrosis of renal tissue. Western blotting, immunohistochemistry and immunofluorescence were used to detect the protein levels of fibrosis-associated proteins and signaling pathway-related proteins. RT-qPCR analysis was used to examine the mRNA levels of related indicators.

Results: EGb significantly decreased the increased levels of Scr, BUN and urinary NAG and attenuated renal damage and the relative area of renal interstitial fibrosis induced by cisplatin. Additionally, EGb decreased the protein levels of α-SMA, Col I, TGF-β1, SMAD2/3, phosphorylated (p)-smad2/3, p38 MAPK, and p-p38 MAPK; the ratio of p-p38 MAPK/p38 MAPK; and the mRNA level of p38 MAPK in renal tissues induced by cisplatin. In agreement with in vivo studies, EGb significantly reduced the increased protein levels of these indicators. Additionally, EGb significantly reduced the increased protein levels of vimentin, TIMP-1, and CTGF, as well as the mRNA levels of α-SMA, vimentin, and TGF-β1, while it significantly increased the reduced E-cadherin protein level and the MMP-1/TIMP-1 ratio in HK-2 cells induced by cisplatin. It's worth noting that the effects of SIS3 in changing the above indicators were similar to those of EGb.

Conclusion: Our study demonstrated that EGb improved cisplatin-induced chronic renal interstitial fibrosis, and its mechanisms were associated with inhibiting the epithelial-mesenchymal transition of renal tubular epithelial cells via the SMAD3/TGF-β1 and SMAD3/p38 MAPK pathways.

Keywords

Cisplatin; Epithelial-mesenchymal transition; Ginkgo biloba leaf extract; Renal interstitial fibrosis; Smad3/TGF- β1; Smad3/p38 MAPK pathway.

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