title: General lysosomal hydrolysis can process prorenin accurately.
abstract: Renin, an aspartyl protease that catalyzes the rate-limiting step of the renin-angiotensin system, is first synthesized as an inactive precursor, prorenin. Prorenin is activated by the proteolytic removal of an amino terminal prosegment in the dense granules of the juxtaglomerular (JG) cells of the kidney by one or more proteases whose identity is uncertain but commonly referred to as the prorenin-processing enzyme (PPE). Because several extrarenal tissues secrete only prorenin, we tested the hypothesis that the unique ability of JG cells to produce active renin might be explained by the existence of a PPE whose expression is restricted to JG cells. We found that inducing renin production by the mouse kidney by up to 20-fold was not associated with the concomitant induction of candidate PPEs. Because the renin-containing granules of JG cells also contain several lysosomal hydrolases, we engineered mouse Ren1 prorenin to be targeted to the classical vesicular lysosomes of cultured HEK-293 cells, where it was accurately processed and stored. Furthermore, we found that HEK cell lysosomes hydrolyzed any artificial extensions placed on the protein and that active renin was extraordinarily resistant to proteolytic degradation. Altogether, our results demonstrate that accurate processing of prorenin is not restricted to JG cells but can occur in classical vesicular lysosomes of heterologous cells. The implication is that renin production may not require a specific PPE but rather can be achieved by general hydrolysis in the lysosome-like granules of JG cells.
authors: Laboratories of Molecular Biochemistry of Hypertension and Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; and.
authors: Lucie K
authors: LK
authors: Xa
authors: Laboratories of Molecular Biochemistry of Hypertension and.
authors: Marie-Josée
authors: MJ
authors: Lacombe
authors: Laboratories of Molecular Biochemistry of Hypertension and.
authors: Chantal
authors: C
authors: Mercure
authors: Neuropeptide Structure and Metabolism, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; and Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors: Claude
authors: C
authors: Lazure
authors: Laboratories of Molecular Biochemistry of Hypertension and Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; and Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors: Timothy L
authors: TL
authors: Reudelhuber
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D003546:Cysteine Endopeptidases; C063281:prorenin processing enzyme; D012083:Renin
keywords: endocrinology; hypertension; lysosomes; proteolysis; renin; renin-angiotensin system