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; 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
Lee, Hewang; Abe, Yoshifusa; Lee, Icksoo et al. (2014) Increased mitochondrial activity in renal proximal tubule cells from young spontaneously hypertensive rats. Kidney Int 85:561-9
Yu, Peiying; Sun, Min; Villar, Van Anthony M et al. (2014) Differential dopamine receptor subtype regulation of adenylyl cyclases in lipid rafts in human embryonic kidney and renal proximal tubule cells. Cell Signal 26:2521-9
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
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
Cuevas, Santiago; Villar, Van Anthony; Jose, Pedro A et al. (2013) Renal dopamine receptors, oxidative stress, and hypertension. Int J Mol Sci 14:17553-72
Felder, Robin A; White, Marquitta J; Williams, Scott M et al. (2013) Diagnostic tools for hypertension and salt sensitivity testing. Curr Opin Nephrol Hypertens 22:65-76
Wang, Xiaoyan; Escano, Crisanto S; Asico, Laureano et al. (2013) Upregulation of renal D5 dopamine receptor ameliorates the hypertension in D3 dopamine receptor-deficient mice. Hypertension 62:295-301