Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice.
Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice.
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DOI：
10.1038/hr.2011.176
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发表时间：
2012-02
影响因子：
5.4
通讯作者：
Yamada, Yuichiro
中科院分区：
文献类型：
--
作者：
Fujita, Hiroki;Fujishima, Hiromi;Morii, Tsukasa;Sakamoto, Takuya;Komatsu, Koga;Hosoba, Mihoko;Narita, Takuma;Takahashi, Keiko;Takahashi, Takamune;Yamada, Yuichiro
关键词：
在高血糖状态下，超氧化物歧化酶(SOD)和超氧化物歧化酶(SOD)是由超氧化物歧化酶和NAD(P)H氧化酶的失衡引起的，可增加氧化应激，促进糖尿病肾病的发生发展。在这项研究中，我们用血管紧张素II 1型受体阻滞剂替米沙坦(5 mg kg−1 )或钙通道阻滞剂氨氯地平(5 mg kg−1 )治疗非肥胖和低胰岛素血症C57BL/6-Akita(C57BL/6-Akita)糖尿病小鼠4周，并比较这两种抗高血压药物对肾脏NAD(P)H氧化酶、超氧化物歧化酶和转录因子NRF2(已知上调包括超氧化物歧化酶在内的几种抗氧化酶)的影响。与野生型非糖尿病小鼠相比，赋形剂处理的C57BL/6-Akita小鼠肾脏NAD(P)H氧化酶活性较高，而肾脏SOD活性较低，肾脏超氧化物歧化酶水平升高。有趣的是，替米沙坦治疗不仅降低了C57BL/6-Akita小鼠肾脏的NAD(P)H氧化酶活性，而且还提高了SOD活性，导致肾脏超氧化物歧化水平降低。此外，替米沙坦治疗的C57BL/6-Akita小鼠增加了肾脏SOD和Nrf2的蛋白表达。在肾超氧化物水平降低的同时，在替米沙坦治疗的C57BL/6-Akita小鼠中，观察到尿白蛋白水平的降低和肾小球滤过率升高的正常化。相比之下，氨氯地平对肾脏NAD(P)H氧化酶、SOD和Nrf2的调节作用不明显。最后，用NAD(P)H氧化酶抑制剂apocynin处理C57BL/6-Akita小鼠，也增加了肾脏SOD和Nrf2的蛋白表达。总之，我们的数据提示，NAD(P)H氧化酶可能通过下调Nrf2来负向调节肾脏SOD，替米沙坦可能通过抑制NAD(P)H氧化酶和随后上调Nrf2而上调肾脏SOD，从而改善肾脏氧化应激和糖尿病肾脏病变。
Renal superoxide excess, which is induced by an imbalance of the superoxide-producing enzyme NAD(P)H oxidase and the superoxide-scavenging enzyme superoxide dismutase (SOD) under hyperglycemia, increases oxidative stress and contributes to the development of diabetic nephropathy. In this study, we treated non-obese and hypoinsulinemic C57BL/6-Ins2Akita (C57BL/6-Akita) diabetic mice with telmisartan (5 mg kg−1 per day), an angiotensin II type 1 receptor blocker, or amlodipine (5 mg kg−1 per day), a calcium channel blocker, for 4 weeks and compared the effects of these two anti-hypertensive drugs on renal NAD(P)H oxidase, SOD and transcription factor Nrf2 (NF-E2-related factor 2), which is known to upregulate several antioxidant enzymes including SOD. Vehicle-treated C57BL/6-Akita mice exhibited higher renal NAD(P)H oxidase and lower renal SOD activity with increased levels of renal superoxide than the C57BL/6-wild-type non-diabetic mice. Interestingly, telmisartan treatment not only reduced NAD(P)H oxidase activity but also enhanced SOD activity in C57BL/6-Akita mouse kidneys, leading to a reduction of renal superoxide levels. Furthermore, telmisartan-treated C57BL/6-Akita mice increased the renal protein expression of SOD and Nrf2. In parallel with the reduction of renal superoxide levels, a reduction of urinary albumin levels and a normalization of elevated glomerular filtration rate were observed in telmisartan-treated C57BL/6-Akita mice. In contrast, treatment with amlodipine failed to modulate renal NAD(P)H oxidase, SOD and Nrf2. Finally, treatment of C57BL/6-Akita mice with apocynin, an NAD(P)H oxidase inhibitor, also increased the renal protein expression of SOD and Nrf2. Collectively, our data suggest that NAD(P)H oxidase negatively regulates renal SOD, possibly by downregulation of Nrf2, and that telmisartan could upregulate renal SOD by the suppression of NAD(P)H oxidase and subsequent upregulation of Nrf2, leading to the amelioration of renal oxidative stress and diabetic renal changes.
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