Pharmacological and non-pharmacological approaches to prevent hypertension-induced renal disease in the spontaneously hypertensive rate

Abstract

Hypertension affects 50 million Americans and remains the second leading cause of renal failure in the United States. Current pharmacological and non-pharmacological approaches to treat hypertension have proven effective, but the complexities of the disease and its renal effects warrant the need for new treatments. The hypothesis of this dissertation was that pharmacological or non-pharmacological approaches to reducing inflammation and oxidative stress would prevent hypertension-induced renal injury in the spontaneously hypertensive rat (SHR). In the first study, we blocked the inflammatory transcription factor, nuclear factor-kappa B (NF-ĸB), with pyrrolidine dithiocarbamate in the SHR kidney. In treated SHR, blood pressure decreased, renal hemodynamics were preserved, and oxidative stress and inflammation were attenuated at both the cytosolic and mitochondrial levels; suggesting a role for NF-ĸB in potentiating hypertension-induced renal injury. In the second study, we examined the effects of aerobic exercise training on renal oxidative stress and inflammation. Exercised SHR exhibited normalized blood pressure and renal hemodynamics. These effects were attributed to lower NF-ĸB activity and decreased oxidative stress in the SHR kidney. In the third and fourth studies, we examined the effects of diet modification by use of blueberry-enriched diets, since blueberries have one of the highest antioxidant capacities of any fruit or vegetable tested to date. In the third study, we fed stroke-prone SHR high salt and a blueberry-enriched diet for 2 days, 6 weeks, or 12 weeks, and examined renal parameters. The SHR fed the blueberry diet for the 6- or 12-week periods demonstrated lower oxidative stress, lower blood pressure, and preservation of renal hemodynamics. These effects were likely due to a hormetic effect of the blueberries themselves, since rats fed blueberries for 2 days demonstrated higher oxidative stress. In the final study, we added blueberries to a stroke-permissive diet, which accelerates renal damage in SHR. Rats were fed diets for 10 weeks. Rats fed the control diet had severe hypertension, severe oxidative stress, and severe inflammation as evidenced by NF-ĸB activation, and exhibited signs of renal failure. Rats fed the blueberry supplemented diet exhibited decreases in blood pressure, oxidative stress, and inflammation, and also had preserved renal structure and function.