title: Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells.
abstract: We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury.
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: David R
authors.initials: DR
authors.lastname: Emlet
authors.affiliation: Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: Nuria
authors.initials: N
authors.lastname: Pastor-Soler
authors.affiliation: Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: Allison
authors.initials: A
authors.lastname: Marciszyn
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wen
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Hernando
authors.initials: H
authors.lastname: Gomez
authors.affiliation: B&B Microscopes, Limited, Pittsburgh, Pennsylvania.
authors.forename: William H
authors.initials: WH
authors.lastname: Humphries
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Seth
authors.initials: S
authors.lastname: Morrisroe
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jacob K
authors.initials: JK
authors.lastname: Volpe
authors.affiliation: Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; kellum@pitt.edu.|Renal Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism; D015415:Biomarkers; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D000071068:Lipocalin-2 / Q000378:metabolism; D009928:Organ Specificity; D015427:Reperfusion Injury / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D018969:Insulin-Like Growth Factor Binding Proteins; D000071068:Lipocalin-2; C560823:TIMP2 protein, human; C102529:insulin-like growth factor binding protein-related protein 1; D019716:Tissue Inhibitor of Metalloproteinase-2
keywords: IGFBP7; acute kidney injury; and TIMP-2; biomarkers