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ER Stress and Mitochondrial ROS Contribute to the Development of Hypertensive‐Diabetic Nephropathy
Author(s) -
Wang Zhen,
Carmo Jussara M.,
Hall John E.
Publication year - 2016
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.30.1_supplement.740.17
Subject(s) - medicine , diabetic nephropathy , renal function , diabetes mellitus , endocrinology , kidney disease , blood pressure , nephropathy , kidney , urology
Hypertension (HT) is common in diabetes and substantially increases the risk for diabetic nephropathy. Current therapies only slow the progression to end stage renal disease (ESRD) in hypertensive‐diabetic patients rather than halt it. Thus, new insights into the mechanisms of this disease are needed. To investigate the mechanisms by which 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 determine the impact of hypertension plus diabetes in the right kidney (above the coarctation) and normal or slightly reduced blood pressure plus diabetes in the left kidney (below the coarctation). Blood pressures (BP) above and below the AC were measured by telemetry and femoral artery catheter, respectively. Glomerular filtration rate (GFR) and urinary albumin excretion (UAE) in left and right kidneys were measured separately by collecting urine from each kidney to evaluate the change of renal function. To assess the potential roles of ER stress and mitochondrial dysfunction in causing kidney injury, GK rats with AC were treated with the ER stress inhibitor, tauroursodeoxycholic acid (TUDCA, 200 mg/kg/day, i.p., 2 to 8 wks after AC), or Mito‐TEMPO, a mitochondrial targeted antioxidant (0.4mg/kg/day, osmotic mini‐pump, 2 to 6 wks after AC) and BP and renal function were examined. After 6 weeks of 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). The ER stress marker CHOP was increased 2‐fold in the HT‐diabetic right kidney compared to the normotensive‐diabetic left kidney. After 6 wks of TUDCA treatment, CHOP expression from the right kidney was significantly reduced by 47% compared to untreated rats, and BP above the AC was significantly lower (135±4 vs 155±4 mmHg, n=7). TUDCA treatment also increased GFR (0.9±0.1 vs 0.6±0.1ml/min/g of kidney weight, n=6) and decreased UAE (5.6±1.5 vs 18.4±5.8 mg/min, n=4–6) when comparing right kidneys between treated and untreated GK‐AC rats. Mito‐TEMPO treatment for 4 weeks in GK‐AC rats also attenuated the BP increase after AC compared to untreated rats (8± 3 vs 17± 5 mmHg, n=3–9). These results suggest that ER stress and mitochondrial generated ROS may contribute to kidney injury when HT is superimposed on diabetes. Pharmacological inhibition of ER stress and mitochondrial ROS attenuate increases in BP and prevent kidney injury in hypertensive‐diabetic nephropathy. Support or Funding Information Funded by NHLBI‐PO1HL51971, AHA 14POST18160019 and NIGMS P20GM10435776