Angiotensin II type II receptor deficiency accelerates the development of nephropathy in type I diabetes via oxidative stress and ACE2.
Angiotensin II type II receptor deficiency accelerates the development of nephropathy in type I diabetes via oxidative stress and ACE2.
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DOI：
10.1155/2011/521076
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发表时间：
2011
影响因子：
--
通讯作者：
Zhang SL
中科院分区：
文献类型：
--
作者：
Chang SY;Chen YW;Chenier I;Tran Sle M;Zhang SL
由于血管紧张素II (Ang II) II型受体（AT2R）在I型糖尿病中的功能作用尚不清楚，我们假设AT2R参与了减少I型糖尿病对肾脏的影响。我们用低剂量链脲佐菌素（STZ）诱导12周龄AT2R敲除（AT2RKO）和野生型（WT）雄性小鼠患糖尿病，并随访4周。研究了非糖尿病、糖尿病和胰岛素治疗糖尿病（Rx胰岛素植入）三个亚组。评估收缩压（SBP）、生理参数、肾小球滤过率（GFR）、肾脏形态、基因表达和细胞凋亡。糖尿病4周后，与WT对照组相比，AT2RKO小鼠明显表现出早期糖尿病肾病（DN）的特征，如肾肥大、肾小管凋亡、进行性细胞外基质（ECM）蛋白积累以及GFR升高。AT2RKO小鼠出现高血压，不受糖尿病影响。在AT2RKO小鼠肾近端小管（RPTs）中，肾脏氧化应激（以血红素加氧酶1 （HO-1）基因表达和活性氧（ROS）产生来测量）和肾内肾素血管紧张素系统成分，如血管紧张素原（Agt）、AT1R和血管紧张素转换酶（ACE）基因表达增强，而血管紧张素转换酶2 （ACE2）基因表达降低。上述肾脏变化在糖尿病AT2RKO小鼠中显著增强，但在胰岛素治疗的糖尿病WT和AT2RKO小鼠中部分减弱。综上所述，AT2R缺乏加速了DN的发展，这似乎是通过RPTs中氧化应激和ACE/ACE2比值升高介导的，至少部分介导。
Since the functional role(s) of angiotensin II (Ang II) type II receptor (AT2R) in type I diabetes is unknown, we hypothesized that AT2R is involved in decreasing the effects of type I diabetes on the kidneys. We induced diabetes with low-dose streptozotocin (STZ) in both AT2R knockout (AT2RKO) and wild-type (WT) male mice aged 12 weeks and followed them for 4 weeks. Three subgroups nondiabetic, diabetic, and insulin-treated diabetic (Rx insulin implant) were studied. Systolic blood pressure (SBP), physiological parameters, glomerular filtration rate (GFR), renal morphology, gene expression, and apoptosis were assessed. After 4 weeks of diabetes, compared to WT controls, AT2RKO mice clearly developed features of early diabetic nephropathy (DN), such as renal hypertrophy, tubular apoptosis, and progressive extracellular matrix (ECM) protein accumulation as well as increased GFR. AT2RKO mice presented hypertension unaffected by diabetes. Renal oxidative stress (measured as heme oxygenase 1 (HO-1) gene expression and reactive oxygen species (ROS) generation) and intrarenal renin angiotensin system components, such as angiotensinogen (Agt), AT1R, and angiotensin-converting enzyme (ACE) gene expression, were augmented whereas angiotensin-converting enzyme2 (ACE2) gene expression was decreased in renal proximal tubules (RPTs) of AT2RKO mice. The renal changes noted above were significantly enhanced in diabetic AT2RKO mice but partially attenuated in insulin-treated diabetic WT and AT2RKO mice. In conclusion, AT2R deficiency accelerates the development of DN, which appears to be mediated, at least in part, via heightened oxidative stress and ACE/ACE2 ratio in RPTs.
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