More than half of the renin in human plasma and nearly half of the renin in human kidney is inactive. Human inactive renin is a putative biosynthetic precursor of active renin. The syndrome of hyporeninemic hypoaldosteronism in diabetes mellitus provides a natural example where a defect in conversion of inactive to active renin appears to result in an inability to initiate the cascade of events leading to angiotensin II production. The consequence is a secondary defect in aldosterone production and hyperkalemia. Our general hypothesis is: 1) plasma and tissue inactive renin is prorenin 2) conversion of prorenin to active renin may be a regulatory step in renin production, 3) several proteolytic steps may be involved in conversion of prorenin yield high MW active renin yield low MW active renin, 4) clinical defects in renin production may result from abnormal renin activation.
Specific aims i nclude: 1) purification and sequence analysis of active and inactive renin in order to determine their exact biochemical relationship. Availability of pure enzymes will allow generation of poly- and monoclonal antibodies for development of specific radioimmunoassays and for immunohistochemical studies and allow radiolabelling for investigation of activation and metabolism in vivo; 2) investigation of renin production in normal man with particular emphasis on determining whether prostaglandins and on the Beta-adrenergic system, relatively independent regulators of renin secretion, enhance conversion of inactive to active renin. The suppressive effects of calcium and angiotensin II will also be examined; 3) Investigation of renin production in diabetes mellitus and hyporeninemic hypoaldosteronism which includes measurement of renin levels, immunohistochemical staining, and analysis of renin activating capacity in renal tissue of HH and control patients; evaluation of effects of stimulatory maneuvers in HH patients which in normals increase active renin and decrease inactive renin (i.e. vasodilating prostaglandins); and determination of the prevalence of a defect in renin activation in diabetes mellitus and relating this to blood pressure, degree of diabetic control, renal function, and presence of diabetic vasular disease.
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