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 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 (BP) in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 wks of AC, BP above the AC (and in the right kidney) increased from 109±1 to 152±5 mmHg in GK rats and from 106±4 to 141±5 mmHg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared to left kidneys (diabetes 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 (TUDCA) for 6 wks reduced BP (135±4 vs 151±4 mmHg), albumin excretion, ER and oxidative stress, glomerular injury, while increasing GFR in hypertensive-diabetic kidneys. These results suggest that diabetes and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress.

Hypertension and Diabetes Mellitus

“…Schematic of the developed approach and proposed synergistic effects of diabetes and hypertension on the kidney (adopted from 3 ). As shown in this figure, increased blood pressure (BP) followed aorta constriction (AC) in non-diabetic kidney and normal BP in diabetic kidneys conditions result in mild kidney injury.…”

“…In this issue of the Hypertension , Wang and colleagues explored interactions of hypertension and diabetes, and their contribution to kidney injury 3 . This study is highly significant from both conceptual and technical perspectives.…”

The Unfolded Protein Response: A Novel Insight into Chronic Kidney Disease (CKD)

“…The coexistence of diabetes mellitus and hypertension increases the risk for onset and progression of chronic renal diseases. 12 Wang et al showed that diabetes mellitus and hypertension interact synergistically to promote oxidative stress and ER stress, thereby leading to progressive renal injury in a rat model of mild type 2 diabetes mellitus combined with hypertension. 12 Treatment of hypertensive-diabetic rat with ER stress inhibitor, tauroursodexycholic acid (TUDCA) for 6 weeks decreases blood pressure, proteinuria, glomerular injury, and oxidative stress, while increasing glomerular filtration rate in the kidneys, suggesting that diabetes mellitus and hypertension synergistically cause renal dysfunction and injury via induction of ER stress.…”

“…12 Wang et al showed that diabetes mellitus and hypertension interact synergistically to promote oxidative stress and ER stress, thereby leading to progressive renal injury in a rat model of mild type 2 diabetes mellitus combined with hypertension. 12 Treatment of hypertensive-diabetic rat with ER stress inhibitor, tauroursodexycholic acid (TUDCA) for 6 weeks decreases blood pressure, proteinuria, glomerular injury, and oxidative stress, while increasing glomerular filtration rate in the kidneys, suggesting that diabetes mellitus and hypertension synergistically cause renal dysfunction and injury via induction of ER stress. 12 Autophagy functions as a pivotal protein degradation machinery that degrades and removes misfolded and aggregated proteins and damaged organelles under both physiological and pathological conditions.…”

“…12 Treatment of hypertensive-diabetic rat with ER stress inhibitor, tauroursodexycholic acid (TUDCA) for 6 weeks decreases blood pressure, proteinuria, glomerular injury, and oxidative stress, while increasing glomerular filtration rate in the kidneys, suggesting that diabetes mellitus and hypertension synergistically cause renal dysfunction and injury via induction of ER stress. 12 Autophagy functions as a pivotal protein degradation machinery that degrades and removes misfolded and aggregated proteins and damaged organelles under both physiological and pathological conditions. 9 Activated UPR targets ubiquitinated misfolded and aggregated proteins to autophagosome for degradation under ER stress.…”