Abstract
Oxidative stress has been widely implicated in both hypertension and chronic kidney disease (CKD). Hypertension is a major risk factor for CKD progression. In the present study we have investigated the effects of chronic single tempol (membrane-permeable radical scavenger) or losartan (angiotensin II type 1 receptor blocker) treatment, and their combination on systemic oxidative status (plasma thiobarbituric acid-reactive substances (pTBARS) production, plasma antioxidant capacity (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid, pABTS), erythrocyte antioxidant enzymes activities) and kidney oxidative stress (kTBARS, kABTS, kidney antioxidant enzymes activities), kidney function and structure in spontaneously hypertensive rats (SHR) with the early course of adriamycin-induced nephropathy. Adult SHR were divided into five groups. The control group received vehicle, while the other groups received adriamycin (2 mg/kg, i.v.) twice in a 21-day interval, followed by vehicle, losartan (L,10 mg/kg/day), tempol (T,100 mg/kg/day) or combined T+L treatment (by gavage) during a six-week period. Adriamycin significantly increased proteinuria, plasma lipid peroxidation, kidney protein oxidation, nitrite excretion, matrix metalloproteinase-1 (MMP-1) protein expression and nestin immunostaining in the kidney. Also, it decreased kidney antioxidant defense, kidney NADPH oxidase 4 (kNox4) protein expression and abolished anti-inflammatory response due to significant reduction of kidney NADPH oxidase 2 (kNox2) protein expression in SHR. All treatments reduced protein-to-creatinine ratio (marker of proteinuria), pTBARS production, kidney protein carbonylation, nitrite excretion, increased antioxidant capacity and restored kidney nestin expression similar to control. Both single treatments significantly improved systemic and kidney antioxidant defense, bioavailability of renal nitric oxide, reduced kMMP-1 protein expression and renal injury, thus retarded CKD progression. Losartan improved blood pressure, as well as tubular injury and restored anti-inflammatory defense by reverting kNox2 expression to the control level. Interestingly, tempol was more successful in reducing systemic oxidative stress, proteinuria, kMMP-1 and glomerulosclerosis. However, combined treatment failed to overcome the beneficial effects of single treatments in slowing down the progression of ADR-induced nephropathy in SHR.
Highlights
Oxidative stress and impaired endogenous antioxidant defense are associated with hypertension [1] and chronic kidney disease (CKD) [2]
Rats that are given adriamycin provide an experimental model of the association between proteinuria and loss of renal function [21]
A cumulative dose of adriamycin 4 mg/kg used in the present study induced an early stage of proteinuric nephropathy with massive proteinuria and advanced glomerular sclerosis with capsular adhesion of glomerular tuft and tubulointerstitial lesions in Spontaneously hypertensive rats (SHR) as previously reported [3,5], followed by a significant increase of plasma creatinine level
Summary
Oxidative stress and impaired endogenous antioxidant defense are associated with hypertension [1] and chronic kidney disease (CKD) [2]. SHR that receive adriamycin (ADR, doxorubicin hydrochloride) develop focal segmental glomerulosclerosis [3,5] followed by massive proteinuria (a nephrotic syndrome severity marker), which is tightly associated with the loss of kidney function [3]. Adriamycin leads to direct oxidative injuries of DNA, generates lipid peroxidation [6], induces protein oxidation [7], and impairs endogenous antioxidant defense [2]. Endogenous defense system involved in neutralization of ROS includes antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)
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