Angiotensin II (Ang II) has multiple sites of action and induces diverse types of tissue responses. Although the action of Ang II is believed to be mediated by transmembrane signal transduction mechanisms, accumulating evidence suggests that Ang II may also have a direct nuclear effect. This nuclear action may account, at least in part, for some of the delayed, long term effects of Ang II. The overall goal of this proposal is to study the mechanism of the nuclear effects at the molecular level. We have characterized nuclear Ang II binding sites in the rat liver. In the absence of detergent, Ang II binding sites appear to be a soluble protein that can be released from nuclei by freezing and thawing and which is distinct in physicochemical properties to the membrane bound receptor. Preincubating cAMP activated nuclear extract with Ang II resulted in generation of specific retarded bands after interacting with the regulatory region of renin gene, as revealed by gel retardation assay. The nuclear Ang II effects may be the result of binding of the hormone-receptor complex to a specific DNA sequence, leading to changes in expression of target genes, like that of thyroid and steroid hormones. We will study the regulation of expression of this nuclear receptor. Perturbations which are known to regulate plasma Ang II receptors will be employed to determine if plasma and nuclear receptors are regulated in parallel. The sequence necessary to confer angiotensin responsiveness to a gene will be determined using molecular biological techniques. We will also study the origin of intracellular Ang II which binds to the nuclear receptor. The results of these studies should greatly increase our understanding on the mechanism of action of this important peptide.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043131-05
Application #
3361600
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1990-09-01
Project End
1995-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Ingelfinger, J R; Jung, F; Diamant, D et al. (1999) Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback. Am J Physiol 276:F218-27
Brem, A S; Bina, R B; Fitzpatrick, C et al. (1999) Glucocorticoid metabolism in proximal tubules modulates angiotensin II-induced electrolyte transport. Proc Soc Exp Biol Med 221:111-7
Amoah-Apraku, B; Chandler, L J; Harrison, J K et al. (1995) NF-kappa B and transcriptional control of renal epithelial-inducible nitric oxide synthase. Kidney Int 48:674-82
Amoah-Apraku, B; Tang, S S; Ingelfinger, J R et al. (1995) Guanosine triphosphate cyclohydrolase I regulates nitric oxide synthesis in renal proximal tubules. J Am Soc Nephrol 5:1630-3
Guzman, N J; Fang, M Z; Tang, S S et al. (1995) Autocrine inhibition of Na+/K(+)-ATPase by nitric oxide in mouse proximal tubule epithelial cells. J Clin Invest 95:2083-8
Tang, S S; Jung, F; Diamant, D et al. (1995) Temperature-sensitive SV40 immortalized rat proximal tubule cell line has functional renin-angiotensin system. Am J Physiol 268:F435-46
Lopez, J J; Lorell, B H; Ingelfinger, J R et al. (1994) Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts. Am J Physiol 267:H844-52
Tang, S S; Jung, F; Diamant, D et al. (1994) Immortalized rat proximal tubule cell lines expressing components of the renin-angiotensin system. Exp Nephrol 2:127
Schunkert, H; Jackson, B; Tang, S S et al. (1993) Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 87:1328-39
Jung, F F; Bouyounes, B; Barrio, R et al. (1993) Angiotensin converting enzyme in renal ontogeny: hypothesis for multiple roles. Pediatr Nephrol 7:834-40

Showing the most recent 10 out of 11 publications