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Interaction of Hypertension and Diabetes in Progressive Nephropathy: Role of ER Stress
Author(s) -
Wang Zhen,
Carmo Jussara,
Williams Jan,
Silva Alexandre,
Hall John
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.959.9
Subject(s) - tauroursodeoxycholic acid , medicine , endocrinology , diabetic nephropathy , diabetes mellitus , kidney , renal function , blood pressure , nephropathy , excretion , type 2 diabetes , unfolded protein response , endoplasmic reticulum , chemistry , biochemistry
To investigate the mechanisms by which hypertension (HT) and diabetes interact to promote nephropathy, 6 month‐old male Goto‐Kakizaki (GK) rats, a model of spontaneous type 2 diabetes, were used in this study. HT was induced by aorta coarctation (AC) between the renal arteries to produce HT plus diabetes in the right kidney (above AC) and normal blood pressure (BP) plus diabetes in the left kidney (below AC). Eight weeks after AC, BP above the AC and urinary albumin excretion (UAE) were significantly increased from baseline (BP: 155±4 vs 108±2 mmHg; UAE: 39.2±14.8 vs 0.9±0.7 mg/24h, n=6, p<0.05). We also observed 17% and 15% increase in protein expression of endoplasmic reticulum (ER) stress markers CHOP and GRP 78 in the HT‐diabetic right kidney compared to the normotensive‐diabetic left kidney. To examine the role of ER stress in development of nephropathy, GK‐AC rats were treated with ER stress inhibitor, tauroursodeoxycholic acid (TUDCA, 200 mg/kg/day IP), from 2 to 8 wks after AC. After 6 wks of treatment, GRP‐78 expression was significantly reduced in the right HT kidney compared to untreated rats. TUDCA treatment lowered BP above the AC (135±4 vs 155±4 mmHg, n=7, p <0.05 compared to untreated group). Also, when comparing right kidneys between treated and untreated GK‐AC rats, TUDCA increased glomerular filtration rate (0.9±0.1 vs 0.6±0.1ml/min/g of kidney weight, n=6, p <0.05) and decreased UAE (5.6±1.5 vs 18.4±5.8 ug/min, n=4‐6, p <0.05). These results suggest that ER stress contributes to kidney injury when HT is superimposed on diabetes. Pharmacological inhibition of ER stress may attenuate increases in BP and kidney injury in hypertensive‐diabetic nephropathy. (NHLBI PO1HL51971, NIGMS P20GM104357, AHA 14POST18160019)