Apocynin and catalase prevent hypertension and kidney injury in Cyclosporine A-induced nephrotoxicity in rats

Yong Chia Tan,Vikneswaran Murugaiyah,Ahmad F Ahmeda,Gurjeet Kaur,Ashfaq Ahmad,Munavvar Abdul Sattar,Nurzalina Abdul Karim Khan,Mohammed Hadi Abdulla,Edward James Johns,Zurina Hassan,Partha Mukhopadhyay

doi:10.1371/journal.pone.0231472

Abstract

Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.

Highlights

Cyclosporine A (CsA) is a potent immunosuppressant agent that is widely used in solid organ transplantation
Treatment of CsA rats with apocynin and apocynin plus catalase but not catalase alone resulted in greater water intake compared to untreated rats (Fig 2)
Urine volume did not change during the study period in all groups except for CsA rats where a significant reduction (P

Summary

Introduction

Cyclosporine A (CsA) is a potent immunosuppressant agent that is widely used in solid organ transplantation. CsA use is associated with several unwanted side effect including nephrotoxicity and hypertension [1]. The incidence of chronic kidney disease (CKD) due to the use of calcineurin inhibitors (CNIs) such as CsA was reported in a cohort study of nonkidney transplant recipients (mostly liver, heart, and lung) [2]. CsA prevents the de-phosphorylation of calcineurin and blocks the cellular mechanisms required for up-regulation of mRNA expression. These effects of CsA regulate the synthesis of many lymphokine mediators such as IL-2 and interferon-ɤ which is critical for T-lymphocyte proliferation and maturation, and macrophage activation [5]

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