The long-term objective of this research project is to identify and define the regulation of renin secretion (RS) at the cellular level. A mounting body of indirect evidence supports the hypothesis that a wide variety of known hemodynamic, ionic, and neurohormonal factors modulate RS by altering the cytosolic free Ca in the juxtagolomerular (JG) cells. The hypothesis holds specifically that RS is inversely related to Free Calcium, consequently a wide variety of baroreceptor (stretch), macula densa (adenosine?), and neurohormonal (alpha - Beta-adrenergic agonists and angiotensin II, ANP, and ADH) factors control RS by regulating the level of Free Calcium.
The specific aims of this proposal are to use a recently developed enriched population of freshly isolated JG cells and: 1) To determine the Free Calcium by the fluorescent Ca-sensitive indicator, Quin-2, and to determine whether the predicted changes, based upon the above hypothesis, in Free Calcium and RS are obtained in response to pressure (stretch), adenosine, isoproterenol and forskolin, angiotensin II, and ADH, organic Ca-channel blockers (nitrendipine, verapamil, diltiazem, and D-600), and ANP. 2) To study the mode of action of Free Calcium on the renin secretory process. This will be approached by first considering whether H+ and Mg++ may be the intracellular ions responsible for RS, instead of Free Calcium. The protonophore, CCCP (for H+), and the divalent cationophore, A23187 (for Mg++) will be used for these studies. This aspect will also examine whether the inhibitory effect of high Free Calcium involves a calmodulin-dependent pathway. The calmodulin antagonists, trifluoperazine, calmidazolium, and W-7, will be used in these studies. 3) To clarify the interaction between the Free Calcium and cyclic AMP pathways in the control of RS. There is some controversy as the the relative importance of Free Calcium and cyclic AMP as final messengers in the control of RS. Some workers hold that Free Calcium is primary and cyclic AMP plays an intermediary role in the Free Calcium cascade, whereas others see a reversal of this order; still other workers have suggested that Free Calcium and cyclic AMP proceed by parallel pathways. This proposal will attempt to settle this controversy and advance our knowledge of the messenger systems involved in the control of RS from freshly isolated JG cells. In general, knowledge gained from these studies will be useful in clarifying our understanding of the mechanism controlling the secretion of renin, an enzyme known to play an important role in several physiological and pathological conditions.
| Malik, B; Jamieson Jr, G A; Ball Jr, W J (1993) Identification of the amino acids comprising a surface-exposed epitope within the nucleotide-binding domain of the Na+,K(+)-ATPase using a random peptide library. Protein Sci 2:2103-11 |
| Park, C S; Honeyman, T W; Ha, S K et al. (1991) Mechanisms of ionophore-induced stimulation of renin secretion with special reference to a chemiosmotic hypothesis. J Pharmacol Exp Ther 259:211-8 |
| Park, C S; Doh, P S; Lee, C J et al. (1991) Cellular mechanism of stimulation of renin secretion by the mercurial diuretic mersalyl. J Pharmacol Exp Ther 257:219-24 |
| Fray, J C; Russo, S M (1990) Mechanism for low renin in blacks: studies in hypophysectomised rat model. J Hum Hypertens 4:160-2 |
| Park, C S; Doh, P S; Carraway, R E et al. (1990) Stimulation of renin secretion by ethacrynic acid is independent of Na(+)-K(+)-2Cl- cotransport. Am J Physiol 259:F539-44 |
| Fray, J C (1990) Control of renin secretion by extracellular calcium. Cell Calcium 11:339-41 |
