title: Distinct role of matrix metalloproteinase-3 in kidney injury molecule-1 shedding by kidney proximal tubular epithelial cells.
abstract: Tubulointerstitial injury is a common pathway in progressive renal impairment and human proximal tubular epithelial cells (PTEC) play a crucial role in this process. Kidney injury molecule-1 (KIM-1) has received increasing attention due to its potential utility as the therapeutic target and biomarker for kidney injury. This study aims to explore the underlying mechanism regulating the release of KIM-1. Cultured primary human PTEC expressed and released KIM-1 from the apical surface through an ectodomain shedding process mediated by matrix metalloproteinase (MMP), independent of gene expression and protein synthesis. The constitutive KIM-1 shedding by PTEC was enhanced in a dose- and time-dependent manner by human serum albumin (HSA) or tumor necrosis factor-α (TNF-α), two important physiological stimuli found during kidney injury. Data from PCR array screening of MMPs gene expression in PTEC following activation by HSA or TNF-α, and from blocking experiments using either synthetic MMP inhibitors or MMP gene knockdown by siRNA, revealed that the constitutive and accelerated shedding of KIM-1 in cultured PTEC was mediated by MMP-3. Furthermore, the up-regulation of MMP-3 and KIM-1 release by PTEC was associated with generation of reactive oxygen species. In a mouse model of acute kidney injury induced by ischemia and reperfusion, increased expression of MMP-3 and KIM-1 as well as their co-localization were observed in kidney from ischemic but not in sham-operated mice. Taken together, these in vitro and in vivo evidences suggest that MMP-3 plays an inductive role in KIM-1 shedding by PTEC.
authors.affiliation: Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Ai Ing
authors.initials: AI
authors.lastname: Lim
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
authors.forename: Chui Wa
authors.initials: CW
authors.lastname: Chow
authors.forename: Man Fai
authors.initials: MF
authors.lastname: Lam
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020868:Gene Silencing; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000201:enzymology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D019278:Matrix Metalloproteinase 3