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 5

CKD phenotype in Kim1RECtg.

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CKD phenotype in Kim1RECtg. (A) Focal fibrotic changes at 4 weeks in K...
(A) Focal fibrotic changes at 4 weeks in Kim1RECtg that become progressively more severe with time. Scale bar: 50 μm. (B) AP expression identifies cells that have undergone Cre-mediated recombination. No AP-positive cells were found in fibrotic interstitium. Scale bar: 50 μm. (C) Concentric left ventricular hypertrophy in aged Kim1RECtg, trichrome stain. (D) Ventricular wall ratio (outer to inner diameter) was increased in aged (range, 12–45 weeks) Kim1RECtg (n = 5 for each group). *P = 0.03. (E) Younger Kim1RECtg (n = 3) do not have hypertension, but older Kim1RECtg (n = 5) do develop hypertension. *P = 0.0002. (F) Hematocrit in control (n = 10) or Kim1RECtg (n = 5) mice between 6 and 10 weeks or control (n = 13) and Kim1RECtg (n = 7) mice measured between 10 and 20 weeks of age. *P = 0.001; **P = 0.0001. (G) Total urinary protein is elevated in 8-week-old Kim1RECtg (n = 3–5) but not at 2 or 4 weeks compared with littermate controls (n = 4–6). *P = 0.01. (H) Urinary protein is not elevated in mice with expression of KIM-1 in podocytes alone at either 4 or 8 weeks. (I) Serum creatinine 13- to 20-week-old mice comparing control (n = 12) and Kim1RECtg (n = 8), control (n = 6) and Six2-GC;Z/AP (n = 7), or control (n = 4) and Podocin-Cre;Z/Kim1-AP (n = 4). *P = 0.006, NS. (J) Anemia was seen in Kim1RECtg but not control mice or mice in which KIM-1 was expressed in podocytes. Control refers to mice with neither transgene or 1 transgene for all groups. *P < 0.0001, NS.