Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
J Pharm Pharmacol. 2023 Aug 1;75(8):1076-1085. doi: 10.1093/jpp/rgad019.
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.
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.
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.
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.
氧化应激介导的黏菌素肾毒性与核因子红细胞 2 相关因子 2（Nrf2）活性降低有关，而 Nrf2 活性主要与细胞 PH 结构域和富含亮氨酸重复蛋白磷酸酶（PHLPP2）水平相关。本研究探讨了瑞舒伐他汀（RST）通过调节 PHLPP2/蛋白激酶 B（Akt）途径作为 Nrf2 稳定性的关键调节剂，从而防止黏菌素诱导的大鼠肾氧化损伤的可能性。
连续 6 天每天腹腔注射黏菌素（300,000 IU/kg），同时大鼠经口给予 RST10 或 20mg/kg 治疗。
RST 通过免疫组织化学染色增强了肾核 Nrf2 的易位，从而增强了肾抗氧化剂超氧化物歧化酶（SOD）和还原型谷胱甘肽（GSH）的表达，并显著降低了 caspase-3。因此，RST 治疗的大鼠表现出正常肾功能和组织学特征的显著恢复。在分子水平上，RST 有效降低了 PHLPP2 的 mRNA 表达，从而促进了 Akt 的磷酸化。因此，它使 GSK-3β失活，并降低了肾组织中 Fyn 激酶的基因表达。
RST 通过抑制 PHLPP2 来增强 Nrf2 活性，从而调节 Akt/GSK3β/Fyn 激酶途径，可减轻黏菌素诱导的急性肾氧化损伤。
