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 #
5R01DK090918-04
Application #
8521272
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$322,178
Indirect Cost
$112,290
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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Natarajan, Aruna R; Eisner, Gilbert M; Armando, Ines et al. (2016) The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans. J Am Soc Nephrol 27:265-79
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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
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
Li, Fengmin; Yang, Jian; Jones, John Edward et al. (2015) Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells. Endocrinology 156:2211-21

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