Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity

Biomed Pharmacother. 2023 Dec:168:115446. doi: 10.1016/j.biopha.2023.115446. Epub 2023 Oct 31.

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.

Keywords: Apoptosis; Bimatoprost; Colistin; Drug repurposing; Nephrotoxicity; Oxidative stress.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / toxicity
  • Bimatoprost / metabolism
  • Bimatoprost / pharmacology
  • Colistin* / pharmacology
  • Dinoprost* / metabolism
  • Female
  • Humans
  • Kidney
  • Mice
  • Mice, Inbred C57BL
  • Prostaglandins / metabolism

Substances

  • Colistin
  • Bimatoprost
  • Dinoprost
  • Anti-Bacterial Agents
  • Prostaglandins