Oral administration of oleuropein attenuates cisplatin‐induced acute renal injury in mice through inhibition of ERK signaling

• Published in: Molecular nutrition & food research 2016-03, Vol.60 (3), p.530-541
• Main Authors: Potočnjak, Iva, Škoda, Marko, Pernjak‐Pugel, Ester, Peršić, Martina Pavletić, Domitrović, Robert
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - prevention & control; Administration, Oral; Animals; Antineoplastic Agents - adverse effects; antioxidants; Apoptosis; Apoptosis - drug effects; blood serum; body weight; caspase-3; cisplatin; Cisplatin - adverse effects; Cisplatin nephrotoxicity; creatinine; cytochrome P-450; Enzyme Inhibitors - pharmacology; heme oxygenase (biliverdin-producing); histopathology; Inflammation; intraperitoneal injection; Iridoids - administration & dosage; Iridoids - pharmacology; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; kidneys; Male; males; MAP Kinase Signaling System - drug effects; MAPK; mice; Mice, Inbred BALB C; mitogen-activated protein kinase; Nephritis - chemically induced; Nephritis - drug therapy; Nephritis - metabolism; Oleuropein; oral administration; oxidative stress; Oxidative Stress - drug effects; phosphorylation; poisoning; prostaglandin synthase; Protective Agents - pharmacology; transcription factor NF-kappa B; tumor necrosis factor-alpha; urea nitrogen
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201500409

SCOPE: Oleuropein possesses numerous health beneficial effects. We investigated the renoprotective effects of oleuropein against cisplatin (CP) induced kidney injury. METHODS AND RESULTS: Male BALB/cN mice were orally gavaged with 5, 10 and 20 mg oleuropein/kg body weight for 2 days, 48 h after intraperitoneal injection of CP (13 mg/kg). Four days after CP administration, serum creatinine and blood urea nitrogen (BUN) levels were significantly elevated, with histopathological changes in renal tissue. In addition, renal oxidative stress was evidenced by increased expression of 3‐nitrotyrosine (3‐NT), 4‐hydroxynonenal (4‐HNE), cytochrome P450 E1 (CYP2E1) and heme oxygenase‐1 (HO‐1). The expression of nuclear factor‐kappaB (NF‐κB) p65, phospho‐p65, tumor necrosis factor‐alpha (TNF‐α) and cyclooxygenase‐2 (COX‐2) in the kidneys increased upon CP treatment, suggesting renal inflammation. CP intoxication increased the expression of p53, Bax and caspase‐3 and induced apoptosis in the kidneys. CP administration also resulted in enhanced phosphorylation of extracellular signal‐regulated kinases 1 and 2 (ERK1/2). All these effects were dose dependently diminished by oleuropein. Oral administration of PD0325901, an MEK inhibitor, coincided with the oleuropein‐mediated suppression of apoptotic, inflammatory and antioxidant markers. CONCLUSION: The results of the current study suggest that oleuropein attenuated CP‐induced acute renal injury, which was mediated through the inhibition of ERK signaling.