Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California.
Departments of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California.
Am J Physiol Renal Physiol. 2018 Apr 1;314(4):F531-F542. doi: 10.1152/ajprenal.00523.2017. Epub 2017 Nov 29.
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.
糖尿病肾病是发达国家终末期肾病的主要病因。血管紧张素转换酶（ACE）抑制剂被用于治疗糖尿病肾病，但肾内 ACE 如何导致糖尿病肾损伤尚不清楚。在这里，研究了两种具有不同肾脏 ACE 表达模式的小鼠模型，以确定肾小管 ACE 与肾小球 ACE 对早期糖尿病肾病的具体贡献：it-ACE 小鼠，其产生内皮 ACE，但缺乏肾小管上皮细胞的 ACE 表达；ACE 3/9 小鼠，其缺乏内皮 ACE，仅在肾小管上皮细胞中表达肾 ACE。内皮 ACE 的缺失使糖尿病 ACE 3/9 小鼠的肾小球滤过率和内皮损伤正常化。然而，这些小鼠发生了肾小管损伤和白蛋白尿，并表现出低肾水平的 megalin，与糖尿病野生型小鼠观察到的相似。在糖尿病 it-ACE 小鼠中，尽管存在高滤过，但肾脏小管 ACE 的缺失大大减少了肾小管间质损伤和白蛋白尿，并增加了与糖尿病野生型和糖尿病 ACE 3/9 小鼠相比的肾脏 megalin 表达。这些发现表明，内皮 ACE 是肾小球滤过率的核心调节剂，而肾小管 ACE 是肾小管损伤和白蛋白尿发展的关键因素。这些数据表明，肾小管损伤而不是高滤过是早期糖尿病肾病微量白蛋白尿的主要原因。
