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 #
5R01DK090918-03
Application #
8335394
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
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$333,863
Indirect Cost
$116,363
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
Armando, Ines; Asico, Laureano D; Wang, Xiaoyan et al. (2018) Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice. Hypertens Res 41:489-498
Li, Fengmin; Yang, Jian; Villar, Van Anthony M et al. (2018) Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 61:727-737
Asico, Laureano D; Cuevas, Santiago; Ma, Xiaobo et al. (2018) Nephron segment-specific gene expression using AAV vectors. Biochem Biophys Res Commun 497:19-24
Armando, Ines (2017) News From the Heart Natriuretic System. Circ Cardiovasc Genet 10:
Diao, Zhenyu; Asico, Laureano D; Villar, Van Anthony M et al. (2017) Increased renal oxidative stress in salt-sensitive human GRK4?486V transgenic mice. Free Radic Biol Med 106:80-90
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
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
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
Armando, Ines; Villar, Van Anthony M; Jose, Pedro A (2015) Genomics and Pharmacogenomics of Salt-sensitive Hypertension. Curr Hypertens Rev 11:49-56

Showing the most recent 10 out of 29 publications