Blood pressure (BP) continuously fluctuates while RBF and GFR do not due to intra-renal adjustments including inhibition of PT reabsorption. This alters NaCI delivery to the macula densa and renin release and contributes to pressure natriuresis, thus, influences BP set point. We have previously established that the decrease in PT Na+ reabsorption is mediated by a retraction of transport competent Na+/H+ exchangers (NHE3) from the PT microvilli, that the response is chronically activated in the Spontaneously Hypertensive Rat (SHR), and that the converse is evident in Renal Injury (RI) hypertension where SNS activation moves NHE3 into the microvilli, potentially contributing to hypertension by counteracting BP mediated inhibition of PT Na+ transport. This progress sets the groundwork for addressing the molecular mechanisms governing NHE3 redistribution in distinct models of acute and chronic hypertension: the source and destination of NHE3, whether there are changes in NHE3 associated proteins and NHE3 activity/transporter en route, and the signals governing redistribution.
Aim 1 tests the hypotheses that NHE3 retraction from the villi during acute hypertension involves a two step process within the apical surface membrane (1) from villi to intermicrovillar cleft, (2) then to intermicrovillar coated pits associated with a change in NHE3 interacting proteins, membrane domain properties, Na+/H+ exchanger activity/transporter, and coincident movement of myosin VI.
Aim 2 tests the hypotheses that during chronic hypertension there are persistent shifts in NHE3 distribution within the apical domain that can be either compensatory, as in the SHR, or contributory, as in the chronic RI model both associated with distinct chronic changes in NHE3 associated proteins, domain properties and activity/transporter.
This Aim also tests the hypothesis that these changes are reversed/normalized when BP is normalized.
Aim 3 tests the hypotheses that Step 1 of NHE3 retraction is dependent on the intrarenal release of nitric oxide that a decrease in Ang II is important for Step 2, and that during acute RI driven by SNS activation NHE3 is recruited from the IMC and ICP regions to the microvilli, rather than by regulated exocytosis. Accomplishing these Aims will reveal how NHE3, the major high capacity renal Na+ transporter, is regulated in vivo by an acute change in blood pressure in the normal range and how it is regulated when BP is chronically elevated by genetics or injury induced SNS activation.
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