Tanimoto Mitsuo, Fan Qiuling, Gohda Tomohito, Shike Toshihide, Makita Yuichiro, Tomino Yasuhiko
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
Metabolism. 2004 Nov;53(11):1473-9. doi: 10.1016/j.metabol.2004.06.016.
Pioglitazone (PIO) has preventive effects on impaired glucose tolerance (IGT) and urinary albumin excretion in diabetes. These effects in the early stage of diabetic nephropathy have not been fully described. Endothelial constitutive nitric oxide synthase (ecNOS) might be one of the mechanisms of glomerular hyperfiltration. The objective of the present study was to evaluate the effect of PIO, including the role of ecNOS on the early stage of diabetic nephropathy in KK/Ta mice. KK/Ta mice were given PIO (10 mg/kg/d) started at 12 or 16 weeks of age for 8 or 4 weeks, respectively. They were divided into 3 groups as follows: early treatment (n = 8), late treatment (n = 8), and control group (n = 12). The urinary albumin/creatinine ratio (ACR), fasting and casual blood glucose levels, ratio of glomerular and Bowman's capsule volume (GB ratio), and systemic blood pressure were measured as phenotypic characterizations. The ecNOS and iNOS protein expression in glomeruli were evaluated by immunofluorescence. PIO, especially early treatment, improved the ACR and the GB ratio, and ecNOS protein expression was decreased in the endothelium of glomerular vessels. The iNOS protein was not detectable. There were no significant changes in the levels of fasting and casual blood glucose and systemic blood pressure among all groups. We conclude that the effect of PIO on microalbuminuria might not be due to changing systemic blood pressure and blood glucose levels. It appears that the decrease of urinary albumin excretion might be related to improvement of glomerular enlargement, including hyperfiltration, since the levels of ecNOS protein were reduced by PIO in the glomerular vessels.
吡格列酮（PIO）对糖尿病患者的糖耐量受损（IGT）和尿白蛋白排泄具有预防作用。糖尿病肾病早期的这些作用尚未得到充分描述。内皮型一氧化氮合酶（ecNOS）可能是肾小球高滤过的机制之一。本研究的目的是评估PIO的作用，包括ecNOS在KK/Ta小鼠糖尿病肾病早期的作用。KK/Ta小鼠在12周或16周龄时分别给予PIO（10mg/kg/d），持续8周或4周。它们被分为以下3组：早期治疗组（n = 8）、晚期治疗组（n = 8）和对照组（n = 12）。测量尿白蛋白/肌酐比值（ACR）、空腹和随机血糖水平、肾小球与鲍曼囊体积比（GB比）以及全身血压作为表型特征。通过免疫荧光评估肾小球中ecNOS和iNOS蛋白的表达。PIO，尤其是早期治疗，改善了ACR和GB比，并且肾小球血管内皮中的ecNOS蛋白表达降低。未检测到iNOS蛋白。所有组之间的空腹和随机血糖水平以及全身血压没有显著变化。我们得出结论，PIO对微量白蛋白尿的作用可能不是由于改变全身血压和血糖水平。似乎尿白蛋白排泄的减少可能与肾小球增大的改善有关，包括高滤过，因为PIO使肾小球血管中ecNOS蛋白水平降低。
