Inhibition of endoplasmic reticulum stress attenuates aorta coarctation induced hypertension and kidney injury in diabetic Goto Kakizaki rats (LB724)

Abstract

Hypertension (HT) is common in diabetes and substantially increases the risk for diabetic nephropathy. 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 produce HT plus diabetes in the right kidney (above AC) and normal blood pressure (BP) plus diabetes in the left kidney (below AC). BP above AC increased to 151±8 mmHg 8 wks after AC (n=5, p<0.05 compared to baseline of 108±5 mmHg). To examine the role of endoplasmic reticulum (ER) stress in the development of hypertensive‐diabetic nephropathy, GK‐AC rats were treated with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 200 mg/kg/day, IP) from 2 to 8 wks after AC. After 6 wks of treatment, ER stress marker, GRP‐78, was significantly reduced in the right HT kidney compared to the right HT kidney from untreated rats. TUDCA treatment also significantly lowered the BP above the AC (137±7 vs 151±8 mmHg, n=4, p<0.05 compared to untreated group). Glomerular filtration rate in the right HT kidney was increased to 0.99 ml/min/g of kidney weight in the TUDCA treated group compared to 0.67 ml/min/g in the untreated group (n=4, p<0.05). TUDCA treatment for 6 weeks also attenuated renal glomerular injury including thickness of glomerular basement membrane and expansion of mesangial matrix on the right HT kidney. These results suggest that ER stress contributes to kidney injury when HT is imposed on the diabetic kidney. Pharmacological inhibition of ER stress may attenuate increases in BP and kidney injury in hypertensive‐diabetic nephropathy.Grant Funding Source: Supported by NHLBI PO1 HL51971, NIGMS P20GM104357, AHA 14POST18160019