Sugama Ikuko, Kohagura Kentaro, Yamazato Masanobu, Nakamura Takuto, Shinzato Tomoko, Ohya Yusuke
Department of Cardiovascular Medicine, Nephrology and Neurology, University of the Ryukyus School of Medicine, Okinawa, Japan.
J Hypertens. 2014 Mar;32(3):534-41. doi: 10.1097/HJH.0000000000000064.
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.
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.
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.
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.
本研究旨在确定抗氧化治疗是否能缓解晚期高血压大鼠的高血压并延缓肾损伤进展。
用超氧化物歧化酶模拟物tempol、低剂量或高剂量坎地沙坦（一种血管紧张素受体阻滞剂）或肼屈嗪对24周龄的自发性高血压易卒中大鼠进行8周治疗，比较血压和肾损伤情况。
8周后出现血压升高和异质性肾损伤，近髓肾单位的肾小球硬化比浅表肾单位更严重。虽然tempol和坎地沙坦均有效降低了肾脏中的活性氧生成，但tempol并未降低血压，反而加重了尿蛋白和组织学损伤，如肾小球硬化和间质纤维化，尤其是在近髓肾单位（tempol组与未治疗组比较：肾小球硬化指数，2.0对1.5，P<0.01；纤维化，15%对10%，P<0.001）。相反，高剂量坎地沙坦和肼屈嗪在降低血压的同时预防了这些形式的肾损伤。低剂量坎地沙坦在未降低血压的情况下也预防了这种肾损伤。此外，tempol治疗的大鼠近髓皮质中大小不同的肾小球数量增加，提示肾小球血流动力学改变可能是肾小球硬化加重的原因。坎地沙坦和肼屈嗪治疗的大鼠肾小球大小均略有减小。
这些结果表明，在晚期开始的单一抗氧化治疗对高血压可能无效，反而会加重无盐负荷的SHRSP的肾损伤。此外，降低血压和抑制肾素-血管紧张素系统对于延缓晚期高血压肾损伤的进展可能至关重要。
