Salt-sensitive (SS) individuals on high Na+ intake not only develop hypertension but also kidney injury/ chronic kidney disease (CKD) and cardiovascular disease (CVD). A reduction in Na+ intake may prevent and treat hypertension, CVD, and CKD. However, low Na+ intake may not always be beneficial in the treatment of hypertension or CVD. A low Na+ intake is associated with increased risk of hypertension (i.e., inverse salt sensitivity (ISS), CVD, and death. Hypertension and diabetes are the major causes of renal injury, accounting for up to 75% of end-stage renal disease. However, hypertension may cause CKD only in the genetically susceptible. In 13 of 16 studies in the GEO Dataset of CKD patients, dopamine type 2 receptor (D2R) gene (DRD2) expression is lower in those with CKD than those without CKD. A decrease in the expression or function of D2R, per se, or caused by DRD2 variants, increases renal inflammation, renal fibrosis, and ISS. The mechanisms/genetics of ISS are not well understood. Mice with global germline deletion of Drd2 (Drd2-/-) have SS hypertension and ISS. However, mice with renal proximal tubule (RPT)-specific conditional deletion of Drd2 (Drd2cPT) have increased blood pressure (BP) only when Na+ intake is decreased, a case of ISS. Sprague- Dawley rats have ISS, related to an increase in the activity of the angiotensin type 1 receptor (AT1R) and α1-adrenoceptors. About 15% of hypertensive subjects have ISS and some associated with DRD2 rs6276/rs6277. Renal-selective expression of DRD2 variant rs6277 in mice should increase BP and impair inhibition of renal Na+ transport and excretion. We will test the overall hypothesis that DRD2/Drd2 is important in preventing ISS by mitigating overly active renin-angiotensin and sympathetic nervous systems and the increase in RPT Na+ transport on a low Na+ diet. Specific Aim 1 will test the hypothesis that in Drd2-/- or Drd2cPT mice, BP increases when Na+ intake is “low”, a case of ISS. The increase in BP in Drd2-/- or Drd2cPT mice fed a low Na+ diet is caused by impaired D2R inhibition of RPT Na+ transport and an increase in RPT Na+ transport caused by activation of both the renin-angioten-sin and sympathetic nervous systems. In the long-term, renal function is decreased because of unmitigated renal fibrosis. Specific Aim 2 will test the hypothesis that DRD2 variants, rs6276/rs6277, decrease D2R expression that is dependent on the effects of the transcription factors NR4a2 and miR4301. These studies are significant and important because they may lead to the identification of the human population that would be adversely affected by the current recommendation to decrease the Na+ intake in everyone.

Project Narrative Salt sensitivity of blood pressure, with or without hypertension, is associated with increased cardiovascular risk and overall mortality; reduction in NaCl consumption is a treatment of salt sensitivity. However, decreasing salt intake in some may actually increase the increased risk for hypertension, and cardiovascular and renal diseases and death. Identifying genes that cause salt sensitivity and, in this proposal, inverse salt sensitivity would be a step towards precision medicine.