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Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity

 Lina Joo  ;  Hye Yun Jeong  ;  Dong Hyuck Bae  ;  Joo Hyun Jee  ;  Woo Hee Choi  ;  Hye-Youn Kim  ;  Sejoong Kim  ;  Dong-Ho Yang  ;  Heon Yung Gee  ;  SeongGyeong Jeon  ;  Yun-Gil Roh  ;  Jongman Yoo 
 BIOMEDICINE & PHARMACOTHERAPY, Vol.168 : 115446, 2023-12 
Journal Title
Issue Date
Animals ; Anti-Bacterial Agents / toxicity ; Bimatoprost / metabolism ; Bimatoprost / pharmacology ; Colistin* / pharmacology ; Dinoprost* / metabolism ; Female ; Humans ; Kidney ; Mice ; Mice, Inbred C57BL ; Prostaglandins / metabolism
Apoptosis ; Bimatoprost ; Colistin ; Drug repurposing ; Nephrotoxicity ; Oxidative stress
Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye-Youn(김혜연) ORCID logo https://orcid.org/0000-0003-2090-6427
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
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