Azadirachta indica (AI) is a medicinal plant with antioxidant properties and cardio‐protective potentials. We investigated the protective potential of polyphenol‐rich fraction (PRF) of the methanol‐extract of AI against Nω‐Nitro‐L‐Arginine Methyl Ester (L‐NAME) induced hypertension and cardiorenal dysfunction in rats. Fifty (50) Wistar albino rats were grouped into five groups. Group A was the control group, given clean water ad libitum and rat cubes only while Group B rats received L‐NAME only at 40 mg/kg body weight orally. Rats in groups C and D received L‐NAME at 40 mg/kg body weight orally in addition to AI at 100 mg/kg and 200 mg/kg body weight respectively, while group E rats were treated with L‐NAME at 40 mg/kg body weight in addition to captopril at 25 mg/kg body weight orally. All treatments were administered for a period of 21 days. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) values were recorded in conscious animals before the termination of the study using a tail cuff blood pressure monitor. The animals were thereafter fasted overnight, sacrificed and the hearts and kidneys were removed from the animals in each group. Biochemical assays to assess the antioxidant defence system and oxidative stress markers were carried out on cardiac and renal tissues. Also, the expressions of Nuclear Erythroid Factor‐2 (Nrf2) in cardiac and renal tissues, as well as Kidney Injury Marker‐I (KIM‐I) in renal tissues were determined by immunohistochemistry. Treatment with L‐NAME caused a significant (p<0.05) increase in the values of the SBP, DBP and MAP. This was ameliorated by the administration of the PRF of AI at the dosages administered as well as captopril. There was a significant (p<0.05) reduction in the activities of antioxidant enzymes (Superoxide dismutase, glutathione peroxidase and Glutathione‐S‐transferase) as well as markers of oxidative stress (protein thiol, non‐protein thiol, malondialdehyde and protein carbonyl) in both cardiac and renal tissues. This was however ameliorated by the administration of AI and captopril. Administration of L‐NAME caused a significant (p<0.05) elevation in the values of plasma creatinine and urea but this was also ameliorated by the administration of AI and captopril. There were lower expressions of Nrf2 in the cardiac and renal tissues, while the expressions of KIM‐1 were increased in the renal tissues of L‐NAME treated rats. Administration of AI amd captopril caused higher expressions of Nrf2 and lower expressions of KIM‐1. This study suggests that the methanol extract of AI possesses modulatory functions in L‐NAME‐induced hypertension and cardiorenal damage through the restoration of blood pressure parameters comparable with captopril, an improvement in the antioxidant defense system and a reduction in the markers of oxidative stress.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.