Wang Zhen, do Carmo Jussara M, Aberdein Nicola, Zhou Xinchun, Williams Jan M, da Silva Alexandre A, Hall John E
From the Department of Physiology & Biophysics (Z.W., J.M.d.C., N.A., J.E.H.), Mississippi Center for Obesity Research (Z.W., J.M.d.C., N.A., J.E.H.), Department of Pathology (X.Z.), and Department of Pharmacology and Toxicology (J.M.W.), University of Mississippi Medical Center, Jackson; and Barão de Mauá University Center, Ribeirão Preto, São Paulo, Brazil (A.A.d.S.).
Hypertension. 2017 May;69(5):879-891. doi: 10.1161/HYPERTENSIONAHA.116.08560. Epub 2017 Mar 27.
Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes mellitus in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month-old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162±11 and 87±2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 weeks of AC, blood pressure above the AC (and in the right kidney) increased from 109±1 to 152±5 mm Hg in GK rats and from 106±4 to 141±5 mm Hg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared with left kidneys (diabetes mellitus only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid for 6 weeks reduced blood pressure (135±4 versus 151±4 mm Hg), albumin excretion, ER and oxidative stress, and glomerular injury, while increasing glomerular filtration rate in hypertensive-diabetic kidneys. These results suggest that diabetes mellitus and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress.
糖尿病和高血压是慢性肾损伤的主要危险因素，二者共同导致了超过70%的终末期肾病。在本研究中，我们评估了高血压与糖尿病在导致肾功能障碍和损伤中的相互作用以及内质网（ER）应激的作用。通过对6月龄雄性Goto-Kakizaki（GK）2型糖尿病大鼠和对照Wistar大鼠的肾动脉之间进行主动脉缩窄（AC）来诱导高血压。GK大鼠和Wistar大鼠的空腹血糖平均分别为162±11和87±2 mg/dL。AC使右肾（AC上方）产生高血压，左肾（AC下方）血压接近正常，且双肾暴露于相同水平的葡萄糖、循环激素和神经影响。AC 8周后，GK大鼠AC上方（及右肾）的血压从109±1 mmHg升高至152±5 mmHg，Wistar大鼠从106±4 mmHg升高至141±5 mmHg。与GK大鼠的左肾（仅糖尿病）或Wistar-AC大鼠的右肾（仅高血压）相比，GK-AC大鼠的糖尿病高血压右肾白蛋白排泄和组织学损伤增加更为显著。在GK-AC大鼠的糖尿病高血压肾中观察到ER应激和氧化应激指标显著增加。用牛磺熊去氧胆酸抑制ER应激6周可降低血压（135±4 mmHg对151±4 mmHg）、白蛋白排泄、ER和氧化应激以及肾小球损伤，同时增加糖尿病高血压肾中的肾小球滤过率。这些结果表明，糖尿病和高血压通过ER应激协同作用促进肾功能障碍和损伤。
