Renal dopamine-1 receptor defect in hypertension

George Washington University, Washington DC

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Abstract

DESCRIPTION (provided by applicant): We hypothesize that the well accepted role of renal dopamine in eliminating Na+, via the kidney, is assisted by a previously unappreciated role of the enterokine gastrin (secreted from G-cells). We are naming this novel pathway the gastrin-renal dopamine axis. Following a meal with Na+ gastrin is released into the circulation, and taken up by renal tubules where it acts on cholecystokinin B receptors (CCKBRs) to decrease Na+ transport. Gastrin is important in the excretion of an oral Na+ load because mice deleted of the gastrin gene (Gast-/-) or Cckbr do not increase Na+ excretion after an oral Na+ load and have high blood pressure. Renal dopa- mine is critical in the excretion of a Na+ load. Deletion of any of the 5 dopamine receptor genes in mice results in hypertension. Inhibition of renal dopamine synthesis or blockade of D1-like receptors also impairs the natriuretic response to a Na+ load. We will test the overall hypothesis that gastrin and renal dopamine interact to regulate renal Na+ handling and blood pressure. The first specific aim will test the hypothesis that the natriuresis that normally occurs with a Na+ load is abolished with systemic deletion of Gast. Gast-/- mice cannot excrete a Na+ load and develop salt-sensitive hypertension. The second specific aim will test the hypothesis that selective knock- down of Gast in the stomach and duodenum impairs the ability to excrete an oral Na+ load. The third specific aim will test the hypothesis that gastrin, Cckbr, and renal dopamine interact but not without Na+, transport, increasing the ability to excrete a Na+ load. Our discovery of the gastrin-dopamine axis was aided by our new technique that allows selective knockdown of Gast to decrease renal Na+ or dopamine decarboxylase (Ddc) which forms L-DOPA, the immediate precursor of dopamine synthesis, in the stomach and duodenum by the infusion of Gast- or Ddc-specific siRNA into the celiac artery. To study the interaction between the molecular targets for dopamine and gastrin (D1R and CCKBR, respectively), we developed a method to culture renal proximal tubule cells from the urine of salt-resistant and salt-sensitive humans. Determining the cause(s) of salt- sensitive hypertension is important in devising approaches to prevent or treat hypertension.