TY - JOUR
T1 - Compound C Protects Against Cisplatin-Induced Nephrotoxicity Through Pleiotropic Effects
AU - Li, Fanghua
AU - Sun, Anbang
AU - Cheng, Genyang
AU - Liu, Dong
AU - Xiao, Jing
AU - Zhao, Zhanzheng
AU - Dong, Zheng
N1 - Funding Information:
Funding. This work was supported by the National Natural Science Foundation of China (Grant No. 81873611), Science and Technology Innovation Team of Henan (Grant No. 17IRTSTHN020), the Foundation for Leading Personnel of Central Plains of China (Grant No. 194200510006), Hubei Province health and family planning scientific research project (Grant No. WJ2018H191), and Due to the great support from the Youth Foundation of the First Affiliated Hospital of Zhengzhou University (Grant No. 70819).
Funding Information:
This work was supported by the National Natural Science Foundation of China (Grant No. 81873611), Science and Technology Innovation Team of Henan (Grant No. 17IRTSTHN020), the Foundation for Leading Personnel of Central Plains of China (Grant No. 194200510006), Hubei Province health and family planning scientific research project (Grant No. WJ2018H191), and Due to the great support from the Youth Foundation of the First Affiliated Hospital of Zhengzhou University (Grant No. 70819).
Publisher Copyright:
© Copyright © 2020 Li, Sun, Cheng, Liu, Xiao, Zhao and Dong.
PY - 2020/12/23
Y1 - 2020/12/23
N2 - AICAR (Acadesine/AICA riboside) as an activator of AMPK, can protect renal tubular cells from cisplatin induced apoptosis. But in our experiment, the dorsomorphin (compound C, an inhibitor of AMPK) also significantly reduced cisplatin induced renal tubular cells apoptosis. Accordingly, we tested whether compound C can protect cisplatin-induced nephrotoxicity and the specific mechanism. Here, we treated Boston University mouse proximal tubular cells (BUMPT-306) with cisplatin and/or different dosages of AICAR (Acadesine/AICA riboside) or compound C to confirm the effect of AICAR and compound C in vitro. The AMPK-siRNA treated cells to evaluate whether the protective effect of compound C was through inhibiting AMPK. Male C57BL/6 mice were used to verify the effect of compound C in vivo. Both compound C and AICAR can reduce renal tubular cells apoptosis in dose-dependent manners, and compound C decreased serum creatinine and renal tubular injury induced by cisplatin. Mechanistically, compound C inhibited P53, CHOP and p-IREα during cisplatin treatment. Our results demonstrated that compound C inhibited AMPK, but the renal protective effects of compound C were not through AMPK. Instead, compound C protected cisplatin nephrotoxicity by inhibiting P53 and endoplasmic reticulum (ER) stress. Therefore, compound C may protect against cisplatin-induced nephrotoxicity through pleiotropic effects.
AB - AICAR (Acadesine/AICA riboside) as an activator of AMPK, can protect renal tubular cells from cisplatin induced apoptosis. But in our experiment, the dorsomorphin (compound C, an inhibitor of AMPK) also significantly reduced cisplatin induced renal tubular cells apoptosis. Accordingly, we tested whether compound C can protect cisplatin-induced nephrotoxicity and the specific mechanism. Here, we treated Boston University mouse proximal tubular cells (BUMPT-306) with cisplatin and/or different dosages of AICAR (Acadesine/AICA riboside) or compound C to confirm the effect of AICAR and compound C in vitro. The AMPK-siRNA treated cells to evaluate whether the protective effect of compound C was through inhibiting AMPK. Male C57BL/6 mice were used to verify the effect of compound C in vivo. Both compound C and AICAR can reduce renal tubular cells apoptosis in dose-dependent manners, and compound C decreased serum creatinine and renal tubular injury induced by cisplatin. Mechanistically, compound C inhibited P53, CHOP and p-IREα during cisplatin treatment. Our results demonstrated that compound C inhibited AMPK, but the renal protective effects of compound C were not through AMPK. Instead, compound C protected cisplatin nephrotoxicity by inhibiting P53 and endoplasmic reticulum (ER) stress. Therefore, compound C may protect against cisplatin-induced nephrotoxicity through pleiotropic effects.
KW - acute kidney injury
KW - cisplatin
KW - compound C
KW - endoplasmic reticulum stress
KW - p53
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UR - http://www.scopus.com/inward/citedby.url?scp=85099137129&partnerID=8YFLogxK
U2 - 10.3389/fphys.2020.614244
DO - 10.3389/fphys.2020.614244
M3 - Article
AN - SCOPUS:85099137129
SN - 1664-042X
VL - 11
JO - Frontiers in Physiology
JF - Frontiers in Physiology
M1 - 614244
ER -