Aliskiren alleviates doxorubicin-induced nephrotoxicity by inhibiting oxidative stress and podocyte injury

Abstract

Introduction: Doxorubicin (DXR) is one of the most effective and widely used anthracycline antibiotics. However, its clinical application is hampered by toxic effects in many organs. Nephrotoxicity is one of the major side effects of anthracycline antibiotics. This study was designed to investigate the possible protective effects of aliskiren (a direct renin inhibitor) in DXR-induced nephrotoxicity in rats. Materials and methods: Wistar albino rats were intraperitoneally (ip) injected with DXR and renin activity, albumin, total protein, urea, creatinine levels in plasma and ultrastructural changes in podocytes were assessed. Results: Rats subjected to DXR administration had significant (p<0.01) increases in systolic blood pressure, plasma renin activity, plasma concentration of urea, creatinine and tissue malondialdehyde and significant (p<0.01) reductions in plasma concentrations of albumin, total protein and antioxidant defense (reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)) in renal tissues. Furthermore, DXR-induced nephrotoxicity has also been characterized by broadening of podocyte foot processes, enlargement of glomerular basement membrane width and reduction in slit pore diameter. The above effects of DXR were significantly (p<0.01) prevented by aliskiren treatment. Conclusions: These findings revealed that the blockade of renin activity by aliskiren is a promising approach in the treatment of DXR-induced nephrotoxicity.

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

“…So far, there only a few studies investigating about the effect of aliskiren on ADR-induced nephrotoxicity have been published. 19,30,41 They reported that plasma renin activity increased in rats with ADR-induced nephrotoxicity. They also found that ADR-induced nephrotoxicity was manifested by elevation in the plasma levels of BUN and creatinine.…”

“…However, ADR treatment has been shown to activate the renin angiotensin system (RAS). 19,[29][30][31] Furthermore, the effectiveness of blockade of the reninangiotensin system in slowing the progression of proteinuria of kidney diseases is well recognized. Therefore, we investigated the interaction between the RAS and the ADR nephrotoxicity in this study.…”

“…17 Previous studies have also reported that Ang-II plays a key role in the process of ADR-induced nephrotoxicity. [18][19][20] However, studies have suggested that angiotensin-converting enzyme inhibitor 20 and angiotensin receptor blocker 18 exert a protective role against ADR-induced nephrotoxicity. 21,22 Ang-II is able to increase oxidative stress by stimulating the generation of both NO and NAD(P)H oxidase-derived superoxide, thereby enhancing reactive nitrogen species.…”

Aliskiren Protects against Hypercholesterolemia and Oxidative Stress on Isolated Aortae in Cholesterol-Fed Rats

“…This chemotherapeutic agent was found to produce a significant increase in malondialdehyde and a significant inhibition in the activity of glutathione in heart tissue, with a significant rise in the serum levels of lactate dehydrogenase (LDH), TC, triglycerides (TG), LDL and reduction in HDL. Fortunately, this pretreatment with aliskiren provides a protection against all these side effects of DXR with strong evidence evidence that aliskiren pretreatment offered a significant cardio-protection against DXR-induced enzymatic changes and cardiac tissue damage [33].…”

Acute adriamycin-induced cardiotoxicity is exacerbated by angiotension II

“…A new drug of renin angiotensin system (RAS) inhibitors (aliskiren (AL)) is a direct inhibitor of the renin enzyme (Rashikh et al 2012) and is reported to be cardioprotective against acute ADR-induced toxicity in heart (Rashikh et al 2013b) and kidney . In other words, the blockade of the renin activity by aliskiren might be a promising approach in the treatment of ADR-induced toxicity (Rashikh et al 2013a).…”