Protective effect of irbesartan against doxorubicin-induced nephrotoxicity in rats: implication of AMPK, PI3K/Akt, and mTOR signaling pathways

Abstract

Nephrotoxicity is one of the serious undesirable effects related to doxorubicin (DOX). Herein, we have investigated the potential protective effect of irbesartan (IRB) against chronic nephrotoxicity induced by DOX, and the implication of different mechanistic pathways underlying these effects. Rats were treated with either DOX (2.5 mg/kg i.p., 3 times/week) for 2 weeks, and (or) IRB (40 mg/kg, daily) for 3 weeks. IRB prohibited nephrotoxicity induced by DOX, which was evident by the increase in blood urea nitrogen and creatinine levels and histopathological changes. IRB improved DOX-induced alterations in oxidative status by diminishing lipid peroxidation and upregulating the antioxidant enzymes. Also, upon DOX treatment, the renal expression of tumor necrosis factor-α, interleukin-6, and caspase-3 were significantly increased; IRB diminished DOX-induced alterations in these parameters. Moreover, DOX significantly decreased the expression level of AMP-activated protein kinase (AMPK). Meanwhile, DOX induced activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and mammalian target of rapamycin (mTOR) pathways that cross talked with AMPK. On the contrary, IRB successfully counterbalanced all these effects. Collectively, these outcomes suggest that the modulation of AMPK, PI3K, Akt, and mTOR pathways plays a critical role in conferring the protective effects of IRB against DOX nephrotoxicity.

Ginkgo Biloba Extract Alleviates Methotrexate-Induced Renal Injury: New Impact on PI3K/Akt/mTOR Signaling and MALAT1 Expression

“…Furthermore, our results revealed a significant upregulation of the PI3K/Akt/mTOR pathway in MTX-treated rats and this may be explained by what was reported about the capability TGF-β in activating the PI3K/Akt/mTOR pathway [37,38]. Several reports demonstrated the involvement of the PI3K/Akt signaling in the pathogenesis of chemotherapy induced-nephrotoxicity like doxorubicin [11], MTX [5], and cisplatin [39,40]. Controversial results were reported in the PI3K/Akt pathway in different experimental models of induced-kidney injury.…”

“…Some researchers reported its activation in the injured kidney [37,38,39,41,42,43,44] while others reported its downregulation [5,45,46,47,48]. This may be explained by using different animal models, experimental conditions, duration, therapies, phosphorylation sites analyzed, and detection methods in addition to the early and late stages of renal diseases [11,49,50].…”

“…Our study is the first to report the involvement of mTOR activation in MTX-induced nephrotoxicity. Also, it was documented that the mTOR is positively regulated by the PI3K/Akt pathway activation [11]. Its activation played a crucial role in the pathogenesis of different models of kidney diseases as diabetic nephropathy (DN), acute renal injury, and obstructed kidney [9,11,38,42].…”

“…Also, it was documented that the mTOR is positively regulated by the PI3K/Akt pathway activation [11]. Its activation played a crucial role in the pathogenesis of different models of kidney diseases as diabetic nephropathy (DN), acute renal injury, and obstructed kidney [9,11,38,42]. The results of this study showed that MTX could activate TGF-β/PI3K/Akt/mTOR signaling and this pathway was mechanistically activated in other models of DN [9] and CCl4 induced liver injury [51].…”

“…One of the proteins regulated by PI3K/Akt is a serine/threonine kinase known as the mammalian target of rapamycin (mTOR). The activation of the phosphorylated mTOR was reported in renal dysfunction and its inhibition resulted in renal protection [9,10,11].…”