The overall objective of this proposal is to define the mechanism of function and physiological role of tissue renin antiotensin systems. We will test the hypothesis that renin in various tissues functions in a compartmentalized way, and will evaluate the significance of tissue renin- angiotensin systems, particularly that in the vascular system, in the elevation of vascular tone in spontaneously hypertensive rats (SHR) and other animal models of essential hypertension. Preliminary results indicate that hypertension in SHR persists after bilateral nephrectomy, but infusion of a renin inhibitor in the nephrectomized SHR markedly lowers its blood pressure. This finding suggests he importance of extra renal tissue renin. Since it is the secreted angiotensin II (ANG II) which is important in regulating vascular functions rather than the amount of the stored renin or ANG II, we have developed a sensitive method to measure the rate of ANG II release from the Krebs-Ringer perfused vasculatures and kidney. New synthetic and immunological inhibitors of renin, angiotensin receptor and lipophilic converting enzyme inhibitors (ACEI) will be used. Pure rat renin and angiotensinogen will be produced from recombinant DNAs. Using these inhibitors of the renin-angiotensin system, we will address the questions as to whether tissue renin-angiotensin plays the major role in spontaneous hypertension. By using the Krebs-Ringer perfusion system, we will determine the mechanism and control of ANG II production from vasculature, kidney and other renin containing cells. The mechanism by which angiotensinogen gain access to tissue renin will be clarified. Specifically, possible presence of angiotensin receptor or transport system in renin containing cells will be looked for using recombinant angiotensinogen. Whether tissue renin works by an extracellular or intracellular mechanism will be investigated. Intracellular pathway of packaging of renin and ANG II will be studied. The hypothesis that renin packaging takes place by way of 6-phosphymannosyl phosphate binding protein and/or newly discovered microsomal sortase will be tested using enriched JG and other types of cells. These studies will clarify the role and mechanism of action of tissue renin which has been unclear to date and expected to contribute importantly to our understanding of the mechanism of renin dependent forms of essential hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035323-08
Application #
3349114
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-12-01
Project End
1995-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Yamakawa, T; Tanaka, S; Numaguchi, K et al. (2000) Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension 35:313-8
Inagami, T; Eguchi, S (2000) Angiotensin II-mediated vascular smooth muscle cell growth signaling. Braz J Med Biol Res 33:619-24
Eguchi, S; Iwasaki, H; Hirata, Y et al. (1999) Epidermal growth factor receptor is indispensable for c-Fos expression and protein synthesis by angiotensin II. Eur J Pharmacol 376:203-6
Inagami, T; Kambayashi, Y; Ichiki, T et al. (1999) Angiotensin receptors: molecular biology and signalling. Clin Exp Pharmacol Physiol 26:544-9
Siragy, H M; Senbonmatsu, T; Ichiki, T et al. (1999) Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor. J Clin Invest 104:181-8
Inagami, T (1999) Molecular biology and signaling of angiotensin receptors: an overview. J Am Soc Nephrol 10 Suppl 11:S2-7
Eguchi, S; Iwasaki, H; Inagami, T et al. (1999) Involvement of PYK2 in angiotensin II signaling of vascular smooth muscle cells. Hypertension 33:201-6
Tamura, M; Wanaka, Y; Landon, E J et al. (1999) Intracellular sodium modulates the expression of angiotensin II subtype 2 receptor in PC12W cells. Hypertension 33:626-32
Kitami, Y; Fukuoka, T; Hiwada, K et al. (1999) A high level of CCAAT-enhancer binding protein-delta expression is a major determinant for markedly elevated differential gene expression of the platelet-derived growth factor-alpha receptor in vascular smooth muscle cells of genetically hypertensive rats Circ Res 84:64-73
Yamakawa, T; Eguchi, S; Matsumoto, T et al. (1999) Intracellular signaling in rat cultured vascular smooth muscle cells: roles of nuclear factor-kappaB and p38 mitogen-activated protein kinase on tumor necrosis factor-alpha production. Endocrinology 140:3562-72

Showing the most recent 10 out of 140 publications