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 a1-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.