title: Cathepsin B is not the processing enzyme for mouse prorenin.
abstract: Renin, an aspartyl protease that catalyzes the rate-limiting step in the renin-angiotensin system (RAS), is proteolytically activated by a second protease [referred to as the prorenin processing enzyme (PPE)] before its secretion from the juxtaglomerular cells of the kidney. Although several enzymes are capable of activating renin in vitro, the leading candidate for the PPE in the kidney is cathepsin B (CTSB) due to is colocalization with the renin precursor (prorenin) in juxtaglomerular cell granules and because of its site-selective activation of human prorenin both in vitro and in transfected tissue culture cell models. To verify the role of CTSB in prorenin processing in vivo, we tested the ability of CTSB-deficient (CTSB-/-) mice to generate active renin. CTSB-/- mice do not exhibit any overt symptoms (renal malformation, preweaning mortality) typical of an RAS deficiency and have normal levels of circulating active renin, which, like those in control animals, rise more than 15-fold in response to pharmacologic inhibition of the RAS. The mature renin enzyme detected in kidney lysates of CTSB-/- mice migrates at the same apparent molecular weight as that in control mice, and the processing to active renin is not affected by chloroquine treatment of the animals. Finally, the distribution and morphology of renin-producing cells in the kidney is normal in CTSB-/- mice. In conclusion, CTSB-deficient mice exhibit no differences compared with controls in their ability to generate active renin, and our results do not support CTSB as the PPE in mice.
authors.affiliation: Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mercure
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Lacombe
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Reudelhuber
mesh_terms: D000468:Alkalies / Q000378:metabolism; D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002216:Captopril / Q000494:pharmacology; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism*; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D006869:Hydronephrosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D012083:Renin / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*
chemical_list: D000468:Alkalies; D000806:Angiotensin-Converting Enzyme Inhibitors; D002738:Chloroquine; D002216:Captopril; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D012083:Renin