There is substantial evidence for dysfunction of D1-1 ike receptors in hypertension but the precise D1-likereceptor involved remains to be determined. One reason is the lack of D1-like receptor ligands selective toeither of the D1-like receptor subtype, D1R or D5R This limitation has been overcome by the selectivedeletion of the D1R and D5R gene in mice: disruption of either receptor gene increases blood pressure andproduces hypertension. Data obtained in previous funding period showed that D5-/- mice are hypertensivecaused, in part, by activation of sympathetic nervous system and increased oxidative stress.Dopamine and angiotensin II receptors regulate each other and interact to regulate renal function but it is notknown which D1-like receptor, D1R or D5R, regulates AT1R action. In renal proximal tubule cells, 75% ofD1-like receptor function is afforded by D1R while only 25% is due to D5R. However, D1-like receptorinhibition of renal Na+K+ATPase activity (which is inhibited, in part, by cAMP/PKA) is abrogated and bloodpressure is increased in D5-/- mice, in spite of an intact D1R gene. Because renal AT1R protein is increasedin D5-/- mice, the impairment of D1R action may be due to increased AT1R expression. This in turn causessalt sensitive hypertension. Indeed, the hypertension of D5-/- is aggravated by increased NaCI intake andAT1R blockade normalizes blood pressure of D5-/- mice. In renal proximal tubule cells, D5R but not D1Rdecreases AT1R protein that cannot be explained by a decrease in transcription or translation. The D5R isconstitutively ubiquitinated and 05R stimulation increases ubiquitination of AT1R. Blockade of proteasomesprevents the D5R-mediated decrease in AT1R protein expression. These data are corroborated in HEK-293cells expressing D5R and AT1R. Therefore, the increase in AT1R protein in D5-/- mice may be caused maybe caused by the failure of D5R to down-regulate AT1 R. It is hypothesized that D5R deficiency leads toincreased AT1R expression, sodium sensitivity, and hypertension.
Specific aim 1 will test the hypothesisthat hypertension in D5-/- mice is, in part, caused by increased renal AT1R expression.
Specific aim 2 willtest the hypothesis that the counter regulation of D1-like and AT1Rs are caused by several mechanismsincluding protein/protein interaction and proteasomal degradation. Knowledge of the mechanisms bywhichhypertension develops when D5R function is impaired may lead to the development of targeted therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Moxey-Mims, Marva M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Jiang, Xiaoliang; Zhang, Yanrong; Yang, Yu et al. (2017) Gastrin stimulates renal dopamine production by increasing the renal tubular uptake of l-DOPA. Am J Physiol Endocrinol Metab 312:E1-E10
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
Yang, Jian; Jose, Pedro A; Zeng, Chunyu (2017) Gastrointestinal-Renal Axis: Role in the Regulation of Blood Pressure. J Am Heart Assoc 6:
Yatabe, Midori Sasaki; Iwahori, Toshiyuki; Watanabe, Ami et al. (2017) Urinary Sodium-to-Potassium Ratio Tracks the Changes in Salt Intake during an Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers. Nutrients 9:
Barati, Michelle T; Ketchem, Corey J; Merchant, Michael L et al. (2017) Loss of NHERF-1 expression prevents dopamine-mediated Na-K-ATPase regulation in renal proximal tubule cells from rat models of hypertension: aged F344 rats and spontaneously hypertensive rats. Am J Physiol Cell Physiol 313:C197-C206
Jiang, Xiaoliang; Chen, Wei; Liu, Xing et al. (2016) The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion. PLoS One 11:e0146641
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
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:
Jose, Pedro A (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8
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

Showing the most recent 10 out of 174 publications