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1 Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
2 Medicine-renal, Johns Hopkins University, Baltimore, Maryland, United States; Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
3 Baltimore, Maryland, United States; Medicine-renal, Johns Hopkins University, Baltimore, Maryland, United States
4 Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: hrabb1{at}jhmi.edu.
Severe ischemia reperfusion injury (IRI) predisposes to long term impairment in kidney function both in patients and experimentally through unknown mechanisms. Given emerging evidence implicating lymphocytes in the pathogenesis of early injury to kidney, liver and lung after IRI, we hypothesized that kidney IRI would potentially release or expose normally sequestered antigens that would lead to proliferation of antigen-recognizing lymphocytes. This in turn, would directly participate in progressive kidney injury. To test this hypothesis, we purified splenic lymphocytes from C57BL/6 mice with severe renal IRI or sham operation 6 weeks postischemia and transferred these cells to normal mice. Donor mice with IRI had significant fibrosis and cellular inflammation. The recipient mice were followed for 6 or 12 weeks. Donor lLymphocytes were tracked using Thy1.1 congenic mouse and found to traffic into recipient kidney. 12 weeks after transfer, kidneys from mice which received IRI primed lymphocytes exhibited significantly increased urinary albumin excretion compared to lymphocytes from sham mice. Splenic CD3+, CD4+, CD3+CD25+, and CD4+CD44+ counts were significantly increased in mice after lymphocyte transfer from IRI mice versus mice with lymphocytes from sham mice. These data demonstrate that lymphocytes from IRI mice can traffic to recipient kidney and directly mediate albuminuria. These data identify a novel mechanism by which initial kidney injury predisposes to long term progressive dysfunction, and identify lymphocytes as potential therapeutic targets for progressive renal diseases.
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