Genomes and Genes
Role of Epithelial Chemokines in Kidney Injury-Molecule-1 Induced Renal Fibrosis
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
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Renal Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
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Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
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- Repair of injured proximal tubule does not involve specialized progenitorsBenjamin 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...