Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy
Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy
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DOI：
10.1152/ajprenal.00523.2017
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发表时间：
2018-04-01
影响因子：
4.2
通讯作者：
Giani, Jorge F.
中科院分区：
文献类型：
--
作者：
Eriguchi, Masahiro;Lin, Mercury;Giani, Jorge F.
糖尿病性肾病是发达国家终末期肾脏疾病的主要原因。虽然使用血管紧张素转化酶（ACE）抑制剂来治疗糖尿病性肾病，但尚不确定肾内ACE如何对糖尿病肾脏损伤有效。在这里，研究了两个具有不同模式的肾脏ACE表达模式的小鼠模型，以确定肾小管和肾小球ACE对早期糖尿病性肾病的特定贡献：IT-ACE小鼠，这使得内皮ACE，但缺乏肾管上皮的ACE表达，并且3/9小鼠，缺乏内皮ACE，仅在管状上皮细胞中表达肾脏ACE。糖尿病ACE 3/9小鼠中的肾小球过滤率和内皮损伤的缺乏使肾小球过滤率和内皮损伤标准化。然而，这些小鼠出现了管状损伤和蛋白尿，表现出低肾脏水平的梅加林水平，这些水平与糖尿病性野生型小鼠中观察到的小鼠相似。在糖尿病IT-ACE小鼠中，尽管没有肾小管ACE的缺乏，与糖尿病性野生型和糖尿病ACE 3/9小鼠相比，肾小管ace大大降低了微管间质损伤和蛋白尿以及肾脏梅加林表达的增加。这些发现表明，内皮ACE是肾小球滤过率的中心调节因子，而管状ACE是肾小管损伤和蛋白尿发展的关键参与者。这些数据表明，管状损伤而不是过滤是早期糖尿病性肾病早期微量白蛋白尿的主要原因。
Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.