Insights into the role of PHLPP2/Akt/GSK3β/Fyn kinase/Nrf2 trajectory in the reno-protective effect of rosuvastatin against colistin-induced acute kidney injury in rats.

Autor:	Shafik MS; Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Egypt., El-Tanbouly DM; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt., Bishr A; Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Egypt., Attia AS; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2023 Aug 01; Vol. 75 (8), pp. 1076-1085.
DOI:	10.1093/jpp/rgad019
Abstrakt:	Objectives: Oxidative stress-mediated colistin's nephrotoxicity is associated with the diminished activity of nuclear factor erythroid 2-related factor 2 (Nrf2) that is primarily correlated with cellular PH domain and leucine-rich repeat protein phosphatase (PHLPP2) levels. This study investigated the possible modulation of PHLPP2/protein kinase B (Akt) trajectory as a critical regulator of Nrf2 stability by rosuvastatin (RST) to guard against colistin-induced oxidative renal damage in rats. Methods: Colistin (300,000 IU/kg/day; i.p.) was injected for 6 consecutive days, and rats were treated simultaneously with RST orally at 10 or 20 mg/kg. Key Findings: RST enhanced renal nuclear Nrf2 translocation as revealed by immunohistochemical staining to boost the renal antioxidants, superoxide dismutase (SOD) and reduced glutathione (GSH) along with a marked reduction in caspase-3. Accordingly, rats treated with RST showed significant restoration of normal renal function and histological features. On the molecular level, RST effectively decreased the mRNA expression of PHLPP2 to promote Akt phosphorylation. Consequently, it deactivated GSK-3β and reduced the gene expression of Fyn kinase in renal tissues. Conclusions: RST could attenuate colistin-induced oxidative acute kidney injury via its suppressive effect on PHLPP2 to endorse Nrf2 activity through modulating Akt/GSK3 β/Fyn kinase trajectory. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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