This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Long-term consequences of high blood pressure including stroke, cardiorenal disease, and end-organ damage are, at least in part, due to a systemic and intrarenal activation of the renin angiotensin system. In contrast to the inhibitory effect that angiotensin II (Ang II) exerts on renin synthesized by juxtaglomerular cells, renin produced in distal Nephron segments is stimulated in Ang II-dependant hypertension. A pro-renin/renin receptor ?the (P)RR at the distal Nephron segments may represent a new generation of angiotensin peptides. Interaction of renin and (P)RR at the distal Nephron segments may represent a new paradigm to explain the increased intrarenal generation of angiotensin peptides and may also help to explain the activation of local signaling pathways contributing to renal injury and hypertension. However, the mechanisms involved in the regulation of distal Nephron renin, neither the contribution of its interaction with the (P)RR to the development and progression of the Ang II-dependant hypertension have been elucidated. This study will investigate the mechanisms responsible for the regulation of renin in the distal Nephron segments mediated by the chronic Ang II infusions and the implications of the interaction between renin and (P)RR during changes of dietary salt in Ang II-dependant hypertension by targeting the following specific aims: 1) To determine if chronically increased intrarenal Ang II content enhances renin production in the distal Nephron directly by activation of Ang II type 1 receptor or indirectly by stimulation of sodium Reabsorption via activation of amiloride-sensitive epithelial sodium channels and/or stimulation of aldosterone/specific mineralcorticoid receptors. 2) To determine the effects of changes in dietary salt on renin and the (P)RR in distal Nephron segments during Ang II-dependant hypertension;and 3) To determine whether chronic administration of the specific renin inhibitor Aliskiren, can attenuate the salt sensitivity hypertension and related intrarenal oxidative stress and kidney injury in chronic Ang II-infused rats by inhibition of renin and (P) RR in distal Nephron segments.
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