Objective: The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats.
Methods: Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared.
Results: Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, P < 0.01; fibrosis, 15 vs. 10%, P < 0.001). In contrast, high-dose candesartan and hydralazine prevented these forms of renal damage with lowering blood pressure. Low-dose candesartan also prevented this renal damage without lowering blood pressure. Moreover, there were increased numbers of larger and smaller glomeruli in the juxtamedullary cortex of tempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size.
Conclusion: These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin–angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.
Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa, Japan
Correspondence to Dr Kentaro Kohagura, MD, PhD, Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan. Tel: +81 98 895 1150; fax: +81 98 895 1416; e-mail: firstname.lastname@example.org
Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; Ang II, angiotensin II; ARB, angiotensin receptor blocker; CTGF, connective tissue growth factor; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; RAS, renin–angiotensin system; ROS, reactive oxidative species; RT-PCR, reverse transcription polymerase chain reaction; SHR, spontaneously hypertensive rat; SHRSP, stroke-prone spontaneously hypertensive rat; TGF-β, transforming growth factor-β; WKY, Wistar–Kyoto rat
Received 30 April, 2013
Accepted 30 October, 2013