Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K, Wada J, Makino H
Department of Medicine III, Okayama University Medical School, Japan.
Diabetologia. 1998 Dec;41(12):1426-34. doi: 10.1007/s001250051088.
The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO2/NO3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO2/NO3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration.
据报道，糖尿病肾病中一氧化氮（NO）产生过多，且被认为与肾小球高滤过有关。然而，糖尿病肾病中NO产生的确切机制尚不清楚。在本报告中，我们比较了链脲佐菌素（STZ）诱导的糖尿病大鼠和5/6肾切除大鼠肾组织中内皮细胞一氧化氮合酶（ecNOS）同工型表达的定位，并阐明了ecNOS在糖尿病肾病早期肾小球高滤过中的关键作用。在糖尿病大鼠中，诱导糖尿病后，入球小动脉直径、肾小球体积、肌酐清除率和尿中NO2/NO3增加。然而，出球小动脉未改变。胰岛素或L-NAME治疗可使入球小动脉直径、肾小球体积、肌酐清除率和尿中NO2/NO3恢复正常。糖尿病大鼠入球小动脉和肾小球中ecNOS的表达在疾病早期增加，但在出球小动脉中未改变。胰岛素或L-NAME治疗均可降低入球小动脉和肾小球中ecNOS的表达。相反，在5/6肾切除大鼠的入球和出球小动脉以及肾小球中，ecNOS表达上调，观察到入球和出球小动脉扩张以及肾小球增大。用L-NAME治疗可改善ecNOS表达和小动脉扩张。我们得出结论，在高血糖状态下，ecNOS在入球小动脉和肾小球内皮细胞中增强的NO合成可能导致入球小动脉优先扩张，最终导致肾小球增大和肾小球高滤过。
