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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK039308-25
Application #
8278515
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Moxey-Mims, Marva M
Project Start
1991-07-25
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
25
Fiscal Year
2012
Total Cost
$484,037
Indirect Cost
$97,575
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Gildea, John J; Shah, Ishan T; Van Sciver, Robert E et al. (2014) The cooperative roles of the dopamine receptors, D1R and D5R, on the regulation of renal sodium transport. Kidney Int 86:118-26
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Gildea, John J; Seaton, Joscelyn E; Victor, Ken G et al. (2014) Exosomal transfer from human renal proximal tubule cells to distal tubule and collecting duct cells. Clin Biochem 47:89-94
Yang, Yu; Cuevas, Santiago; Yang, Sufei et al. (2014) Sestrin2 decreases renal oxidative stress, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of reactive oxygen species production. Hypertension 64:825-32
Arnaldo, Francis B; Villar, Van Anthony M; Konkalmatt, Prasad R et al. (2014) D1-like dopamine receptors downregulate Na+-K+-ATPase activity and increase cAMP production in the posterior gills of the blue crab Callinectes sapidus. Am J Physiol Regul Integr Comp Physiol 307:R634-42
Jiang, Xiaoliang; Konkalmatt, Prasad; Yang, Yu et al. (2014) Single-nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells. Hypertension 63:e74-80
Yu, Peiying; Han, Weixing; Villar, Van Anthony M et al. (2014) Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol 2:570-9
Armando, Ines; Villar, Van Anthony M; Jones, John E et al. (2014) Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote NHE3 degradation. FASEB J 28:1422-34

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