Renal injury associated with hypertension, diabetes and the metabolic syndrome is a disease outcome of enormous cost to health and economic resources that, in contrast to other adverse outcomes, is increasing in prevalence. The pathogenesis of renal injury and its progression to end stage renal disease (ESRD) involves the generation of renal oxidative stress and resulting tissue injury. Unfortunately, little is known about the origin of this oxidative stress. It is unclear to what extent increased oxidative free radical production versus reduced free-radical scavenging contribute to the shift in redox balance. Furthermore, since multiple genes and proteins are involved both in radical production and in defense against radical injury, a comprehensive picture of the pattern of changes in these mechanisms as hypertensive renal injury develops is lacking. Our recent work analyzing the progressive changes in renal gene expression in an animal model of heritable hypertension in association with susceptibility to oxidative renal injury has generated two important observations: first, the emergence of renal injury is preceeded by a clear and coordinated down-regulation of many genes involved in reactive radical scavenging;second, this coordinated pattern of functional change appears to be regulated by a single transcription factor abundantly expressed in kidney: hepatocyte nuclear factor 1, HNF1. In the present studies, we will extend our gene array and bioinformatics methods to develop direct evidence supporting this mechanism of renal injury in hypertension by targeting HNF1 expression in vitro and in vivo. We will investigate the role of renal immune cell infiltration in hypertensive renal injury in which activated immune cells may release cytokines that play a key role in HNF1 transcriptional coordination of gene expression to produce redox stress. We will investigate whether the enhancement of renal injury by increased salt intake is attributable to increased oxidative stress mediated by HNF1 transcriptional control. Finally, we will address the role of oxidative stress in heritable susceptibility to renal injury by contrasting its development in two related animal models of hypertension differing in their genetic susceptibility to renal injury.
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