The prevalence of chronic kidney disease is rising sharply worldwide and affects 13.1% of the population in the USA. Hypertension is one of the major causes of renal injury. Low-grade inflammation is associated with cardiovascular disease and specifically with hypertension. Inflammation and oxidative stress are major mediators in the development and progression of renal disease. There is increasing evidence that genetic factors contribute to the susceptibility to renal disease associated with hypertension and it has been suggested that hypertension may cause progressive kidney disease only in genetically susceptible individuals. The genetic predisposition to chronic kidney disease is polygenic but so far only a few genes have been shown to be contributory. This project will test the overall novel hypothesis that the dopamine D2 receptor regulates the inflammatory reaction in the kidney and that impaired function of the D2 receptor results in renal inflammation and end-organ damage. Polymorphisms of the D2 receptor gene are commonly observed in humans and some of them have been associated with elevated blood pressure and even hypertension. Several polymorphisms of the D2 receptor result in decreased expression/function of the receptor. If our hypothesis proves to be correct, then individuals carrying these polymorphisms could be more vulnerable to renal injury when challenged with an insult such as elevated blood pressure. These results could then be critical for designing innovative genetic testing assays and therapeutics.

Public Health Relevance

Genetic factors contribute to the susceptibility to renal disease associated with essential hypertension. Inflammation is crucial in the development of renal injury. This project will test the overall novel hypothesis that impaired function of the dopamine D2 receptor results in renal inflammation and end-organ damage. Several polymorphisms of the D2 receptor result in decreased expression of the receptor or decreased receptor affinity. If our hypothesis proves to be correct, then individuals carrying these polymorphisms could be more vulnerable to renal injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK090918-01A1
Application #
8236580
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2011-09-30
Project End
2012-02-09
Budget Start
2011-09-30
Budget End
2012-02-09
Support Year
1
Fiscal Year
2011
Total Cost
$196,285
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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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:
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4?142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
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Armando, Ines; Villar, Van Anthony M; Jose, Pedro A (2015) Genomics and Pharmacogenomics of Salt-sensitive Hypertension. Curr Hypertens Rev 11:49-56
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
Chandra, Ramesh; Francis, T Chase; Konkalmatt, Prasad et al. (2015) Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action. J Neurosci 35:7927-37
Cuevas, Santiago; Yang, Yu; Konkalmatt, Prasad et al. (2015) Role of nuclear factor erythroid 2-related factor 2 in the oxidative stress-dependent hypertension associated with the depletion of DJ-1. Hypertension 65:1251-7
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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