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.
|Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4Î³142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34|
|Jose, Pedro A; Yang, Zhiwei; Zeng, Chunyu et al. (2016) The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol 101:465-70|
|Sanada, H; Yoneda, M; Yatabe, J et al. (2016) Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. Pharmacogenomics J 16:3-9|
|Liu, Tianbing; Konkalmatt, Prasad R; Yang, Yu et al. (2016) Gastrin decreases Na+,K+-ATPase activity via a PI 3-kinase- and PKC-dependent pathway in human renal proximal tubule cells. Am J Physiol Endocrinol Metab 310:E565-71|
|Jose, Pedro A; Felder, Robin A; Yang, Zhiwei et al. (2016) Gastrorenal Axis. Hypertension 67:1056-63|
|Konkalmatt, Prasad R; Asico, Laureano D; Zhang, Yanrong et al. (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1:|
|Jiang, Xiaoliang; Chen, Wei; Liu, Xing et al. (2016) The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion. PLoS One 11:e0146641|
|Jose, Pedro A (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8|
|Armando, Ines; Konkalmatt, Prasad; Felder, Robin A et al. (2015) The renal dopaminergic system: novel diagnostic and therapeutic approaches in hypertension and kidney disease. Transl Res 165:505-11|
|Han, Fei; Konkalmatt, Prasad; Chen, Jianghua et al. (2015) MiR-217 mediates the protective effects of the dopamine D2 receptor on fibrosis in human renal proximal tubule cells. Hypertension 65:1118-25|
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