Role of Epithelial Chemokines in Kidney Injury-Molecule-1 Induced Renal Fibrosis

Summary

Principal Investigator: Benjamin D Humphreys
Abstract: DESCRIPTION (provided by applicant): A link between acute kidney injury (AKI) and the development of chronic kidney disease (CKD) is increasingly appreciated, but the molecular mechanisms remain obscure. Kidney Injury Molecule-1 (Kim-1) is a phosphatidylserine receptor upregulated only on injured epithelial cells of the kidney where it clears the tubular lumen of apoptotic and necrotic cells after injury. The applicant's K08 grant proposed to investigate the possible contribution of Kim-1 to the development of renal fibrosis with prolonged Kim-1 expression. To do so, the applicant created a transgenic mouse model for the conditional expression of Kim-1 exclusively on renal epithelia. Transgenic mice were healthy and renal histology was normal at birth. Beginning at 4 weeks, a spontaneous and progressive mononuclear infiltrate was observed in Kim-1 expressing kidneys consisting of CD3+ lymphocytes, as well as dendritic cells and macrophages. Older mice developed progressive inflammatory cell infiltration and progressive proteinuria, anemia, renal failure, interstitial fibrosis and death from renal failure by 19 weeks. Kim-1 expression in very young mice was associated with strongly elevated pro-inflammatory chemokine and cytokine expression despite normal tubule histology, suggesting that the mechanism behind this fibrotic response is the Kim-1 dependent recruitment of pro-inflammatory cells to the kidney. These results link epithelial injury, the innate immune system and chronic inflammation and indicate that Kim-1 is not simply a biomarker of disease in humans but is instead a therapeutic target. To probe the mechanism of these clinically relevant findings, we propose in this R03 application to test the hypothesis that Kim-1 expression drives chronic renal fibrosis by recruiting T cells and macrophages to the kidney through epithelial cell production of the chemokines CXCL-1, CXCL-10 and macrophage chemoattract protein-1 (MCP-1). We will test this hypothesis with the following two specific aims: (1) Do Kim-1 positive renal epithelial cells in Kim-1 transgenic mice show evidence of expression of CXCL-1, CXCL-10 and MCP-1? We will use a combination of fluorescence activated cell sorting (FACS), immunofluorescence microscopy and primary epithelial cell culture to assess activation of these pro-inflammatory signals in both Kim-1 transgenic and in wild-type mice subjected to renal injury to induce endogenous Kim-1 protein. (2) Does expression of Kim-1 and/or activation of Kim-1 by phagocytosis trigger acute activation of the NF-kB pathway, resulting in expression of pro-inflammatory signals? We will use two inducible Kim-1 cell culture models and trigger Kim-1 ligation to assess NFkB pathway activation using an ELISA-based assay, western blotting and NFkB transcriptional activity. PUBLIC HEALTH RELEVANCE: The increasing prevalence of chronic kidney disease in our aging population represents an enormous health burden. Because the final common pathway for most chronic nephropathies is renal fibrosis, therapies that reverse or even slow fibrosis would have tremendous clinical impact. These studies will explore the molecular mechanism by which Kim-1 recruits inflammatory cells to the injured kidney and thereby identify a novel pathway that may serve as an important therapeutic target in treating renal fibrosis. The proposed studies are therefore of great public health interest.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis
    Benjamin D Humphreys
    Renal Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Am J Pathol 176:85-97. 2010
  2. pmc Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Kidney Int 82:172-83. 2012
  3. pmc Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 123:4023-35. 2013
  4. pmc The spectrum of kidney involvement in lymphoma: a case report and review of the literature
    Lisa J Cohen
    Nephrology Division, Brigham and Women s Hospital, Boston, MA, USA
    Am J Kidney Dis 56:1191-6. 2010
  5. pmc Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors
    Emily S Robinson
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA, USA
    Hypertension 56:1131-6. 2010
  6. pmc Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker
    Emily S Robinson
    Brigham and Women s Hospital, Boston, Massachusetts, USA
    Semin Nephrol 30:591-601. 2010
  7. pmc The origin of interstitial myofibroblasts in chronic kidney disease
    Ivica Grgic
    Renal Division, Brigham and Women s Hospital, Harvard Institutes of Medicine Rm 550, Boston, MA 02115, USA
    Pediatr Nephrol 27:183-93. 2012
  8. pmc Repair of injured proximal tubule does not involve specialized progenitors
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:9226-31. 2011

Scientific Experts

  • B D Humphreys
  • Lisa J Cohen
  • Ivica Grgic
  • Emily S Robinson
  • S Ananth Karumanchi
  • Eliyahu V Khankin
  • Venkata S Sabbisetti
  • Joseph V Bonventre
  • Gabriela Campanholle
  • Vanesa Bijol
  • Takaharu Ichimura
  • Chang Wang
  • Jeremy S Duffield
  • Toni K Choueiri
  • Mallika S Dhawan
  • Miranda J Rogers

Detail Information

Publications9

  1. pmc Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis
    Benjamin D Humphreys
    Renal Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Am J Pathol 176:85-97. 2010
    ..These data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease...
  2. pmc Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Kidney Int 82:172-83. 2012
    ..Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD...
  3. pmc Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 123:4023-35. 2013
    ..Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease...
  4. pmc The spectrum of kidney involvement in lymphoma: a case report and review of the literature
    Lisa J Cohen
    Nephrology Division, Brigham and Women s Hospital, Boston, MA, USA
    Am J Kidney Dis 56:1191-6. 2010
    ..We discuss a case of non-Hodgkin lymphoma and associated kidney failure from several distinct malignancy-related mechanisms and review the spectrum of lymphoma-related kidney involvement...
  5. pmc Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors
    Emily S Robinson
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA, USA
    Hypertension 56:1131-6. 2010
    ..Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies...
  6. pmc Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker
    Emily S Robinson
    Brigham and Women s Hospital, Boston, Massachusetts, USA
    Semin Nephrol 30:591-601. 2010
    ....
  7. pmc The origin of interstitial myofibroblasts in chronic kidney disease
    Ivica Grgic
    Renal Division, Brigham and Women s Hospital, Harvard Institutes of Medicine Rm 550, Boston, MA 02115, USA
    Pediatr Nephrol 27:183-93. 2012
    ....
  8. pmc Repair of injured proximal tubule does not involve specialized progenitors
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:9226-31. 2011
    ..Thus, nonlethally injured cells repopulate the kidney epithelium after injury in the absence of any specialized progenitor cell population...