title: IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats.
abstract: T cells have been implicated in the pathogenesis of acute kidney injury (AKI) and its progression to chronic kidney disease (CKD). Previous studies suggest that Th17 cells participate during the AKI-to-CKD transition, and inhibition of T cell activity by mycophenolate mofetil (MMF) or losartan attenuates the development of fibrosis following AKI. We hypothesized that T cell-deficient rats may have reduced levels of IL-17 cytokine leading to decreased fibrosis following AKI. Renal ischemis-reperfusion (I/R) was performed on T cell-deficient athymic rats (Foxn1rnu-/rnu-) and control euthymic rats (Foxn1rnu-/+), and CKD progression was hastened by unilateral nephrectomy atday 33and subsequent exposure to 4.0% sodium diet. Renal fibrosis developed in euthymic rats and was reduced by MMF treatment. Athymic rats exhibited a similar degree of fibrosis, but this was unaffected by MMF treatment. FACS analysis demonstrated that the number of IL-17+cells was similar between postischemic athymic vs. euthymic rats. The source of IL-17 production in euthymic rats was predominately from conventional T cells (CD3+/CD161-). In the absence of conventional T cells in athymic rats, a compensatory pathway involving natural killer cells (CD3-/CD161+) was the primary source of IL-17. Blockade of IL-17 activity using IL-17Rc receptor significantly decreased fibrosis and neutrophil recruitment in both euthymic and athymic rats compared with vehicle-treated controls. Taken together, these data suggest that IL-17 secretion participates in the pathogenesis of AKI-induced fibrosis possibly via the recruitment of neutrophils and that the source of IL-17 may be from either conventional T cells or NK cells.
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: Purvi
authors.initials: P
authors.lastname: Mehrotra
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Collett
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: Seth D
authors.initials: SD
authors.lastname: McKinney
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: Jackson
authors.initials: J
authors.lastname: Stevens
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: Carlie M
authors.initials: CM
authors.lastname: Ivancic
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University of Medicine, Indianapolis, Indiana.
authors.forename: David P
authors.initials: DP
authors.lastname: Basile
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D051858:Forkhead Transcription Factors / Q000235:genetics; D005838:Genotype; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D011923:Rats, Nude; D055647:Rats, Transgenic; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D051858:Forkhead Transcription Factors; C515934:Il17a protein, rat; D020381:Interleukin-17; C090140:Whn protein
keywords: lymphocytes; progression