REGULATION OF RENIN AND PREECLAMPTIC HYPERTENSION

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DESCRIPTION: (Adapted from the Investigator's Abstract) Many tissues secrete an inactive pro-form of renin. A 43 amino acid pro- segment removal to produce active renin is believed to occur, primarily in the kidney. Recent data on transgenic mouse model of preeclampsia support a role of reproductive renin in its pathogenesis and our data on increased decidual renin expression in human preeclampsia confirms this role. For renin to have such a functional role, cellular processing to active renin should occur locally. The cellular and molecular aspects of the uterine renin- angiotensin system have not been adequately investigated. Presence of estrogen and progesterone response elements in the promoter of renin gene suggests a role for the sex steroids in the regulation of prorenin expression. Our recent data suggest that progesterone treatment of endometrial stromal cells (in vitro decidualization) increases active renin secretion by increasing prorenin expression and by increasing conversion of prorenin to renin in a hormone- specific manner, and that decidual cells from human gestation process prorenin to renin. Our most recent co-transfection experiment in HEK293 cells and cathepsin B inhibition in decidual cells suggest that cathepsin B may function as a prorenin convertase. We hypothesize that pathologic increase in decidual renin may proximately initiate preeclampsia, and sex steroids may induce expression of prorenin and its proconvertase (PC), thereby regulating mature renin secretion. Therefore, the objectives are: 1) To demonstrate that decidual stromal cells in vitro secrete active mature renin, as assayed by activity and by N terminal sequencing; 2) To identify the decidual cell endoprotease responsible for prorenin activation by (i) northern analysis with probes for PCs and cathepsin B, and (ii) defining constitutive versus regulated renin secretion, and (iii) examining the effect of cathepsin B inhibition on prorenin processing; (b) To examine regulation of endoprotease expression; 3) To confirm that the candidate-activating enzyme is the specific prorenin convertase by (a) immuno-microscopic co-localization with prorenin in the vesicles and (b) functional verification by co-transfection of prorenin and candidate-activating enzyme expression vectors in a standard cell line and demonstration of processing to mature active renin. These studies will improve our understanding of the role of progesterone in the regulation of reproductive renin and may provide a novel direction for investigating the pathophysiology of preeclampsia.