Abstract 611: Interaction of Hypertension and Diabetes in Progressive Nephropathy, Enhanced ER Stress and Mitophagy in Goto Kakizaki Rats

Abstract

Hypertension is common in patients with diabetes and substantially increases the risk for onset of kidney disease and progression of nephropathy. To investigate the molecular mechanisms by which hypertension and diabetes interact to cause nephropathy, 4 month-old male Goto-Kakizaki (GK) rats, a spontaneous type II diabetic model, were implanted with telemetry probes to measure blood pressure (BP) and heart rate (HR) 24-hrs/day. Hypertension was induced by aorta coarctation (AC) between 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). Four weeks after AC, BP above the AC was significantly increased from baseline (111±8 vs. 138±22 mmHg, n=7-9, p <0.05). BP measured in the femoral artery showed there was ~25 mmHg pressure gradient across the AC (n=5). Blood glucose (316±60 vs. 251±93 mg/dL) and HR (292±13 vs. 302±23 bpm) levels did not significantly change after AC. Glomerular filtration rate (GFR) in left and right kidneys at 4 weeks after AC were examined by a split bladder method. GFR was increased in the hypertensive-diabetic right kidney compared to the normotensive-diabetic left kidney (1.8±0.2 vs. 0.9±0.2 ml/min, p <0.05). Associated with increased GFR, right kidney weight was also increased compared to the left kidney (1.9±0.5 vs. 1.4±0.3 g). Marked renal morphological changes such as thickening of glomerular basement membrane, expansion of mesangial matrix were observed in the right kidney. IHC staining for 4-hydroxynonenal, an indicator of lipid peroxidation and oxidative stress, showed a stronger staining in the right kidney than left kidney. We also observed 17% and 15% increased protein expression on endoplasmic reticulum (ER) stress markers CHOP and GRP 78, as well as 20% increased mitophagy marker Beclin 1 in the right kidney compared to the normotensive left kidney. These results suggest that glomerular hyperfiltration and oxidative stress were induced when hypertension interacted with diabetes. Enhanced ER stress and mitophagy may be two major contributors to amplified renal oxidative stress during the progression of hypertensive-diabetic nephropathy. (NHLBI-PO1 HL51971)