Activation of Sirtuin 1 by Ellagic Acid Ameliorates Cisplatin-Induced Apoptosis, Oxidative Stress and Nephrotoxicity

Abstract

Background: Cisplatin (Cis) is a chemotherapeutic agent commonly applied in treating different cancers. However, acute renal injury remains a major side effect of Cis that limits its clinical use. Oxidative stress in renal tissues play a key role in Cis-induced toxicity. This research aimed to investigate the impact of ellagic acid (Ella) on Cis-induced apoptotic renal injury and the possible involvement of sirtuin 1 (SIRT1) and oxidative stress as a possible protective mechanism.
 Methods: Twenty-four Sprague Dawley rats were divided into four groups (n=6) and treated as follows. The control (Cont) group (0.9% saline), Ella group (10 mg/kg), Cis group (7.5 mg/kg), Ella + Cis group (10 mg/kg + 7.5 mg/kg). Ella was administered 7 days prior to Cis injection. Seventy-two hours later, the rats were sacrificed, and blood and kidney samples were collected. Biochemical analyses were performed on serum and kidney homogenate. The histopathological and immunohistochemical analyses were performed on the formalin preserved kidneys.
 Results: Ella significantly decreased serum creatinine and urea levels compared to the Cis group. Furthermore, Ella protects the kidney cortex and medulla against most Cis-induced histopathological changes. Ella significantly decreased kidney contents of malondialdehyde (MDA). Moreover, Ella reversed the Cis-induced reduction of kidney antioxidants, including glutathione peroxidase, superoxide dismutase, and catalase. Ella decreased kidney protein expression of both cyclooxygenase-2 (COX-2) and Bax proteins while increased SIRT1 and Bcl2 expression.
 Conclusion: The results revealed a reduction in SIRT1 protein expression in rat renal medullary and cortical tissues following Cis treatment. However, Ella significantly enhanced SIRT1 expression, antioxidants levels, and reduced Cis-induced apoptosis, inflammation, and oxidative stress by increasing the ratio of Bax/Bcl-2 and reducing the expression of COX-2 and MDA, respectively. These findings provide additional evidence of the antioxidant and antiapoptotic effect of Ella in Cis-induced renal toxicity.

Ellagic acid ameliorates aging-induced renal oxidative damage through upregulating SIRT1 and NRF2

“…Here, we showed that EA administration ameliorated age-associated renal dysfunction and histopathological alterations, which is thought to be mediated through SIRT1. Similar findings of improved renal function and histopathological features mediated by SIRT1 were also reported in several rat models of nephrotoxicity [17,28].…”

“…EA, a natural polyphenolic compound, has received considerable attention because of its various biological properties, such as radical scavenging, anti-inflammatory, antiviral, cancer, and diabetes-prevention activities [14]. A recent study reported that EA administration significantly enhanced the expression of SIRT1 in rat kidneys and ameliorated cisplatin-induced nephrotoxicity [28]. Additionally, EA has been shown to protect renal tissues against iron oxide-induced damage by promoting the expression of SIRT1 [17].…”