Modulation of miR-205/ EGLN2 by rosuvastatin mitigates colistin-induced nephrotoxicity in rats: Involvement of ATF4/ CHOP and Nrf2 pathways.

Autor: Shafik MS; Pharmacology and Toxicology department, Faculty of Pharmacy, Ahram Canadian University, Egypt., Bishr A; Pharmacology and Toxicology department, Faculty of Pharmacy, Ahram Canadian University, Egypt., El-Tanbouly DM; Pharmacology and Toxicology department, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: dalia.eltanbouly@pharma.cu.edu.eg., Attia AS; Pharmacology and Toxicology department, Faculty of Pharmacy, Cairo University, Egypt.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Jan; Vol. 157, pp. 114042. Date of Electronic Publication: 2022 Nov 24.
DOI: 10.1016/j.biopha.2022.114042
Abstrakt: Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.
Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interests.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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