Facilitated By

San Antonio Medical Foundation


UT Health San Antonio

The UT Health San Antonio, with missions of teaching, research and healing, is one of the country’s leading health sciences universities.

Principal Investigator(s)
Stockand, James David
Funded by
Research Start Date

Discretionary control of renal Na+ transport matches renal Na+ excretion with dietary Na+ intake. Because Na+excretion can influence blood pressure, disordered renal Na+ transport in many instances causes abnormalblood pressure. Moreover, as we know from the actions of most diuretics and many tubulopathies interdictionof normal renal Na+ transport changes blood pressure. Renal sodium excretion is fine-tuned in response tohormonal signaling in the aldosterone-sensitive distal nephron (ASDN). Within the ASDN, the activity of theepithelial Na+ channel, ENaC, is the principal mediator of Na+ reabsorption. Consequently, modulation of ENaCactivity is an important regulator of Na+ excretion and blood pressure. ENaC functions as one final effector ofthe renin-angiotensin-aldosterone system (RAAS) during the control of blood pressure. Gain and loss of ENaCfunction, like RAAS, increases and decreases blood pressure by decreasing and increasing renal Na+excretion, respectively. Emerging evidence supports that there are other physiologically important signalingpathways that function in parallel with the RAAS to fine-tune ENaC activity in the ASDN. Previous R01 fundedresearch from my laboratory demonstrated that a purinergic system intrinsic to the distal nephron regulatesENaC activity through inhibitory paracrine signaling via apical membrane metabotropic P2Y2 receptors inprincipal cells. Our findings have shown that this purinergic system is quantitatively important to the regulationof ENaC and perhaps consequently, sodium excretion and blood pressure. The latter, though, is only surmisedhaving been tested indirectly and in a cursory manner. Similar to a gain of ENaC function, dysfunction ofnormal paracrine purinergic inhibition of ENaC is predicted to cause salt-sensitivity and increases in bloodpressure as a result of inappropriate Na+ excretion. In contrast, activation of this system is predicted topromote Na+ excretion. The studies proposed in this resubmission test the premise that inhibitory purinergicregulation of ENaC contributes to the fine-tuning of renal Na+ excretion and consequently, regulation of bloodpressure. These studies will provide mechanistic understanding and offer a high degree of translation to thehuman condition by testing the following three aims: 1) Determine if targeted disruption in the ASDN ofpurinergic signaling increases ENaC activity, decreases Na+ excretion and causes salt-sensitivity; 2)Determine if targeted activation of P2Y2 receptor signaling in the ASDN increases Na+ excretion and canmitigate to some degree forced salt-sensitivity; and 3) Determine if inhibitory purinergic signaling is importantfor ENaC regulation in the human kidney. It is expected that completion of these studies will elaborate aphysiologically important mechanism that contributes to the normal regulation of Na+ excretion; and that whendysfunctional may cause certain forms of salt-sensitivity; and possibly serve as a novel therapeutic target forthe treatment of elevated blood pressure.

Collaborative Project
Basic Research