Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis
Benjamin D. Humphreys, … , Vijay K. Kuchroo, Joseph V. Bonventre
Benjamin D. Humphreys, … , Vijay K. Kuchroo, Joseph V. Bonventre
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):4023-4035. https://doi.org/10.1172/JCI45361.
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Research Article Nephrology

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 (Kim1RECtg) 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, Kim1RECtg 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. Kim1RECtg 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

Benjamin D. Humphreys, Fengfeng Xu, Venkata Sabbisetti, Ivica Grgic, Said Movahedi Naini, Ningning Wang, Guochun Chen, Sheng Xiao, Dhruti Patel, Joel M. Henderson, Takaharu Ichimura, Shan Mou, Savuth Soeung, Andrew P. McMahon, Vijay K. Kuchroo, Joseph V. Bonventre

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Figure 2

Generation and initial characterization of Kim1RECtg mice.

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Generation and initial characterization of Kim1RECtg mice. (A) Schemat...
(A) Schematic of the Z/Kim1-AP transgene used for generation of transgenic mice. (B) Transient transfection of Cos7 cells with the Z/Kim1-AP (Z/Kim1) plasmid in the absence or presence of a plasmid directing expression of a GFPCre fusion protein verifies that LacZ is expressed before Cre-dependent recombination, and AP after. Original magnification, ×400. (C) KIM-1 protein is detected only in lysates of Cos7 cells cotransfected with Z/Kim1-AP and GFPCre plasmids. (D) Wholemount X-gal stain of a Z/Kim1-AP–positive mouse and littermate control (age 4 weeks) shows mosaic LacZ activity throughout cortex. (E) WT mice express neither LacZ nor AP, whereas Z/Kim1-AP mice (age 4 weeks) exhibit mosaic LacZ expression but no AP expression. Kidney sections from bigenic Kim1RECtg mice show reduced LacZ expression and activation of AP expression in the cortex. Scale bar: 250 μm.