Program Director/Principal Investigator (Last, First, Middle): Jose, PedfO A.PROJECT SUMMARY {See instructions):The Dl receptor (DIR) and DSR regulate ion transport in the renal proximal tubule, thick ascending limb,and other nephron segments. In the previous cycle, we showed that that SNX5 and SNX1 are important inthe intemalization of DIR and DSR, respectively. Moreover, selective renal deletion of SNX1 or SNXSincreases blood pressure in mice and rats. In human renal proximal tubule cells, SNXS is expressed in non-lipid rafts while DIR, GRK4, and PP2A-catalytic subunit/ PPP2R2C2, and VPS 26 are in lipid and non-lipidrafts. Dl-like receptor stimulation shifts DIR, GRK4, PP2A catalytic subunit/PPP2R2C2, and VPS 26 tonon-lipid rafts where SNXS is located. We hypothesize that the assembly of DIR with the signaling complexin membrane microdomains is govemed by SNXS. SNXS may act as a chaperone in the intracellulartrafficking of DIR after agonist stimulation. This hypothesis will be tested in human renal proximal tubulecells; mouse proximal and distal convoluted tubule celis will be studied also because the role of theseproteins on renal function and blood pressure will be tested in genetically manipulated mice.
Specific aim 1 will test the hypothesis that SNXS is important in the assembly of DIR, PP2A complex, and GRK4 in non-lipid raft membrane microdomains, as well as the intemalization of this complex after agonist stimulation andsubsequent recycling.
Specific aim 2 will test the hypothesis that Dl R is linked to adenylyl cyclase (AC) IIIand AC VI and DSR is linked to AC IV in specific membrane microdomains in renal proximal tubules. In non-renal proximal tubule cells, D1R is linked to AC V. However, AC V is not expressed in renal proximaltubules.
Specific aim 3 will test the hypothesis that PPP2R2C, SNX1, and SNXS are important in theregulation of blood pressure. These in vitro and in vivo studies may give important information on howspecificity is confened on G protein-coupled receptor action, related to second messengers, sodiumtransport, and subsequently hypertension. At least two hypotheses are novel: 1) that SNXS is important inthe assembly and signaling of DIR, PP2A, AC III and AC VI and GRK4 while DSR is linked to AC IV. Atleast two methods are novel: selective renal gene silencing in mice and inducible/reversible knockout.

Public Health Relevance

(See Instructions):The cause and mechanisms leading to essential hypertension are still not well understood.These studieshave important implication in hypertension because GRK4 gene variants are associated with hypertension;of all the genes thought to be important in hypertension, only the human GRK4 gene variants have beenshown to produce hypertension in mice. SNX1 and PP2R2C gene variants are associated with hypertensionin Caucasian AmericansPROJECT/PERFORMANCE SrrE(S) (if additional space Is needed, use

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37HL023081-32
Application #
8184751
Study Section
Special Emphasis Panel (NSS)
Program Officer
OH, Youngsuk
Project Start
1988-04-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
32
Fiscal Year
2012
Total Cost
$421,852
Indirect Cost
$147,030
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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Yu, Peiying; Han, Weixing; Villar, Van Anthony M et al. (2014) Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells. Redox Biol 2:570-9
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

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