Guo Christine, Martinez-Vasquez Diego, Mendez Gonzalo P, Toniolo Maria F, Yao Tham M, Oestreicher Eveline M, Kikuchi Taisuke, Lapointe Nathalie, Pojoga Luminita, Williams Gordon H, Ricchiuti Vincent, Adler Gail K
Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115, USA.
Endocrinology. 2006 Nov;147(11):5363-73. doi: 10.1210/en.2006-0944. Epub 2006 Aug 10.
To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.
为了确定盐皮质激素受体（MR）激活在糖尿病肾损伤中是否起作用，以及该作用在1型和2型糖尿病中是否存在差异，我们研究了MR拮抗剂对1型（链脲佐菌素处理的大鼠）和2型（db/db小鼠）糖尿病啮齿动物模型肾损伤的影响。我们将三组8周龄、单侧肾切除的Wistar大鼠研究4周：链脲佐菌素（55 mg/kg）处理的糖尿病大鼠（n = 11）、接受MR拮抗剂依普利酮的链脲佐菌素处理的糖尿病大鼠（n = 15）和非糖尿病大鼠（n = 9）。此外，我们将三组8周龄小鼠研究16周：糖尿病db/db小鼠（n = 10）、用依普利酮处理的糖尿病db/db小鼠（n = 8）和非糖尿病的db/+同窝小鼠（n = 11）。糖尿病大鼠和小鼠出现蛋白尿以及肾损伤的组织病理学证据，包括肾小球肥大、系膜扩张、肾小管间质损伤以及肾皮质MR蛋白、MR mRNA、TGFβ mRNA和骨桥蛋白mRNA水平升高。除MR水平升高外，依普利酮治疗可显著减轻所有这些变化。依普利酮的有益作用并非归因于血压或血糖的变化。总之，糖尿病啮齿动物肾脏中MR表达增加，且MR拮抗剂可有效减轻糖尿病肾损伤，而与糖尿病的种类或具体病因无关。因此，这些数据表明MR激活是1型和2型糖尿病肾病早期发病机制中的关键因素。
