Membrane-type 4 matrix metalloproteinase (MT4-MMP) modulates water homeostasis in mice

• Published in: PloS one Vol. 6; no. 2; p. e17099
• Main Authors: Srichai, Manakan B, Colleta, Heloisa, Gewin, Leslie, Matrisian, Linsey, Abel, Ty W, Koshikawa, Naohiko, Seiki, Motoharu, Pozzi, Ambra, Harris, Raymond C, Zent, Roy
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.02.2011; Public Library of Science (PLoS)
• Subjects: Abnormalities; Animals; Biology; Brain research; Cancer; Dilution; Embryogenesis; Embryonic development; Enzymes; Gene Deletion; Gene Expression Regulation, Enzymologic; Glycosylphosphatidylinositol; Homeostasis; Hospitals; Hypodipsia; Hypothalamus; Hypothalamus, Anterior - enzymology; Hypothalamus, Anterior - physiology; Kidney diseases; Kidney Medulla - enzymology; Laboratory animals; Matrix metalloproteinase; Matrix Metalloproteinase 17 - deficiency; Matrix Metalloproteinase 17 - genetics; Matrix Metalloproteinase 17 - metabolism; Medicine; Metalloproteinase; Metastasis; Mice; Morphogenesis; Mouse devices; Nephrology; Osmolar Concentration; Phosphatidylinositol; Physiological aspects; Potassium; Renal function; Rodents; Substrates; Thirst; Transgenic animals; Urine; Water - metabolism; Water intake; Water intakes; United States > US; Tennessee; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017099

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.