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.
The body regulates urinary sodium excretion, via a communication between the gut and the kidney. When sodium is eaten, G-cells in the stomach and duodenum secrete gastrin which helps to increase renal dopamine levels. Gastrin produced outside the gut, acting in an autocrine/paracrine manner, abets the increase in renal dopamine. Gastrin and dopamine, acting on their receptors in the kidney, decrease sodium transport, increasing sodium excretion. Perturbation of these interactions results in hypertension.
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