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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK039308-24
Application #
8452935
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Moxey-Mims, Marva M
Project Start
1991-07-25
Project End
2016-04-30
Budget Start
2012-02-10
Budget End
2012-04-30
Support Year
24
Fiscal Year
2011
Total Cost
$133,542
Indirect Cost
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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