1. Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity.
- Author
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Joo, Lina, Jeong, Hye Yun, Bae, Dong Hyuck, Jee, Joo Hyun, Choi, Woo Hee, Kim, Hye-Youn, Kim, Sejoong, Yang, Dong-Ho, Gee, Heon Yung, Jeon, SeongGyeong, Roh, Yun-Gil, and Yoo, Jongman
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COLISTIN , *BIMATOPROST , *NEPHROTOXICOLOGY , *LIPOCALIN-2 , *PROSTAGLANDINS , *BLOOD urea nitrogen - Abstract
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. [Display omitted] • Colistin treats multidrug-resistant bacterial infections, but its nephrotoxicity risk limits use. • High-Content Screening reveals Bimatoprost as a potential protector against colistin's nephrotoxicity. • Bimatoprost might be a protective drug for nephrotoxicity, its systemic use needs more study. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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