Pathophysiological consequences of excess renal reactive oxygen species production in mineralocorticoid hypertensive rats.

Abstract

Hypertension imparts an increased risk of myocardial infarction, stroke, renal damage, and blindness. Additionally, hypertension causes cellular and hemodynamic changes such as smooth muscle cell proliferation, alteration of vascular reactivity, renal proteinuria and electrolyte imbalance. This dissertation tests the hypothesis that excess ROS production increases systolic blood pressure, renal inflammatory responses and kidney injury in mineralocorticoid hypertensive rats. In hypertension due to elevated angiotensin II levels, it has been reported that angiotensin II caused excess reactive oxygen species (ROS) production, nuclear factor-kappaB (NF-kappaB) activation, and end organ damage. In contrast, we found that in the depressed renin, mineralocorticoid (DOCA-salt) hypertensive rat model, that superoxide (O₂<super> -</super>) production and induction of NF-kappaB could be induced in the absence of angiotensin II. Additionally, chronic treatment of mineralocorticoid hypertensive rats with an antioxidant, to quench excess ROS, resulted in attenuation of blood pressure, renal hypertrophy and the renal inflammatory response. Furthermore, antioxidant treatment caused attenuation of kidney injury in the mineralocorticoid hypertensive rat. Additional studies also revealed that nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase is partially responsible for increased O₂<super> -</super> production in the vasculature and kidney of mineralocorticoid hypertensive rats. In conclusion, the findings of this dissertation show that excess O₂<super>-</super> production contributes to pathophysiological changes observed in the mineralocorticoid hypertensive rat.