Hypertension is a risk factor for the development of end stage renal disease. The mechanisms underlying hypertensive nephropathy are poorly understood. There is, however, evidence that in hypertension there is an accumulation of partially reduced oxygen and its derivatives, known collectively as reactive oxygen species. The central hypothesis of this proposal is that a sustained increment in blood pressure is accompanied by an accumulation of reactive oxygen species, which, in turn, contribute to the progressive renal dysfunction that accompanies salt- sensitive hypertension. This effect is achieved by, or is a consequence of, a reduction in nitric oxide bioavailability. We will address this hypothesis through three specific aims. First, we will characterize the pro-oxidant activity of salt-dependent hypertension in renal tissue, by measuring the production of reactive oxygen species and the change in cellular redox state in kidney homogenates from Dahl salt-sensitive hypertensive, as well as salt-resistant normotensive, rats maintained on normal and high NaCl diets. We will also investigate molecular mechanism(s) involved in the pro-oxidant effect of salt-dependent hypertension, by its correlation with modifications in the activity of the endothelium-derived relaxing factor and the evaluation of changes in the expression of redox-sensitive genes that may regulate nitric oxide bioavailability. Next, we will define the effects of salt- dependent reactive oxygen species accumulation on renal function. In addition, we will attempt to correlate the time-course of renal dysfunction with the rate of reactive oxygen species accumulation. Lastly, we will determine whether acute pharmacological modifications in the activity of those enzymes involved in the generation and metabolism of ROS cause alterations in its accumulation. Drawing from the conclusions of the acute experiments, we will attempt to alter the course of hypertension development and renal dysfunction both by increasing, as well as by impairing, the rate of reactive oxygen species accumulation. With these studies we hope to elucidate the mechanisms of salt-dependent hypertensive nephrosclerosis.
| Forde, Patrick; Scribner, Anne Ward; Dial, Ravina et al. (2003) Prevention of hypertension and renal dysfunction in Dahl rats by alpha-tocopherol. J Cardiovasc Pharmacol 42:82-8 |
| Trolliet, M R; Rudd, M A; Loscalzo, J (2001) Oxidative stress and renal dysfunction in salt-sensitive hypertension. Kidney Blood Press Res 24:116-23 |
