title: Membrane-type 4 matrix metalloproteinase (MT4-MMP) modulates water homeostasis in mice.
abstract: MT4-MMP is a membrane-type metalloproteinase (MMP) anchored to the membrane by a glycosyl-phosphatidylinositol (GPI) motif. GPI-type MT-MMPs (MT4- and MT6-MMP) are related to other MT-MMPs, but their physiological substrates and functions in vivo have yet to be identified. In this manuscript we show that MT4-MMP is expressed early in kidney development, as well as in the adult kidney, where the highest levels of expression are found in the papilla. MT4-MMP null mice had minimal renal developmental abnormalities, with a minor branching morphogenesis defect in early embryonic kidney development and slightly dysmorphic collecting ducts in adult mice. Interestingly, MT4-MMP null mice had higher baseline urine osmolarities relative to wild type controls, but these animals were able to concentrate and dilute their urines normally. However, MT4-MMP-null mice had decreased daily water intake and daily urine output, consistent with primary hypodipsia. MT4-MMP was shown to be expressed in areas of the hypothalamus considered important for regulating thirst. Thus, our results show that although MT4-MMP is expressed in the kidney, this metalloproteinase does not play a major role in renal development or function; however it does appear to modify the neural stimuli that modulate thirst.
authors.affiliation: Department of Medicine, Veterans Administration Hospital, Nashville, Tennessee, United States of America.
authors.forename: Manakan B
authors.initials: MB
authors.lastname: Srichai
authors.forename: Heloisa
authors.initials: H
authors.lastname: Colleta
authors.forename: Leslie
authors.initials: L
authors.lastname: Gewin
authors.forename: Linsey
authors.initials: L
authors.lastname: Matrisian
authors.forename: Ty W
authors.initials: TW
authors.lastname: Abel
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
mesh_terms: D000818:Animals; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D007032:Hypothalamus, Anterior / Q000201:enzymology / Q000502:physiology; D007679:Kidney Medulla / Q000201:enzymology; D053515:Matrix Metalloproteinase 17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009994:Osmolar Concentration; D014867:Water / Q000378:metabolism*
chemical_list: D014867:Water; D053515:Matrix Metalloproteinase 17