title: Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis.
abstract: Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1(RECtg)) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1(RECtg) mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1(RECtg) kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1-dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.
authors: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. bhumphreys@partners.org
authors: Benjamin D
authors: BD
authors: Humphreys
authors: Fengfeng
authors: F
authors: Xu
authors: Venkata
authors: V
authors: Sabbisetti
authors: Ivica
authors: I
authors: Grgic
authors: Said
authors: S
authors: Movahedi Naini
authors: Ningning
authors: N
authors: Wang
authors: Guochun
authors: G
authors: Chen
authors: Sheng
authors: S
authors: Xiao
authors: Dhruti
authors: D
authors: Patel
authors: Joel M
authors: JM
authors: Henderson
authors: Takaharu
authors: T
authors: Ichimura
authors: Shan
authors: S
authors: Mou
authors: Savuth
authors: S
authors: Soeung
authors: Andrew P
authors: AP
authors: McMahon
authors: Vijay K
authors: VK
authors: Kuchroo
authors: Joseph V
authors: JV
authors: Bonventre
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009393:Nephritis / Q000378:metabolism; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators; D008565:Membrane Proteins
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