The current research proposal is based upon observations that (a) glucocorticoids cause vascular smooth muscle angiotensin II (AII) receptor synthesis and AII receptor/ phospholipase C (PLC) uncoupling and (b) apical AII endocytosis is required prior to proximal tubule (PT) PLC activation. The latter observation suggests that AII is internalized to non-plasma membrane PLC activation sites, particularly since AII receptors, PLC and G proteins have been isolated within nuclear membranes. The hypothesis is that AII binds to PT and VSMC plasma membrane receptors, undergoes endocytosis, binds to nuclear AII receptors, and activates nuclear membrane-bound PLC and PLD. One determinant of AII endocytosis is plasma membrane AII receptor number, which is controlled by glucocorticoid-induced increases in PT AII receptor synthesis. Glucocorticoids alter coupling of VSMC AII receptors to PLC through regulation of G proteins and lipocortins.
The specific aims are to determine if (1) nuclear AII receptors are present in VSMC and PT cells, (2) nuclear AII receptors are linked to signaling enzymes in VSMC and PT cells, and (3) mechanisms by which glucocorticoids regulate VSMC and PT cell plasma membrane AII receptor/signal coupling. These experiments are relevant to the role of AII in the pathogenesis of edematous conditions, essential and glucocorticoid-mediated hypertension, since AII is associated with PT Na reabsorption, and glucocorticoids control expression of the angiotensinogen gene, which has recently been linked to essential hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002281-05
Application #
2701037
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1998-05-13
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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