title: Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress.
abstract: 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.
authors.affiliation: 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.). zwang3@umc.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Jussara M
authors.initials: JM
authors.lastname: do Carmo
authors.affiliation: 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.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Aberdein
authors.affiliation: 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.).
authors.forename: Xinchun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.).
authors.forename: Jan M
authors.initials: JM
authors.lastname: Williams
authors.affiliation: 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.).
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: da Silva
authors.affiliation: 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.).
authors.forename: John E
authors.initials: JE
authors.lastname: Hall
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001794:Blood Pressure / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000209:etiology* / Q000503:physiopathology
chemical_list: D001786:Blood Glucose
keywords: blood pressure; glomerular filtration rate; kidney disease; oxidative stress; tauroursodeoxycholic acid; type 2 diabetes mellitus