IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: Compensatory role of natural killer cells in athymic rats

Purvi Mehrotra, Jason A. Collett, Seth D. McKinney, Jackson Stevens, Carlie M. Ivancic, David Basile

Research output: Contribution to journalArticle

19 Citations (Scopus)

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 at day 33 and 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.

Original languageEnglish (US)
Pages (from-to)F385-F397
JournalAmerican Journal of Physiology - Renal Physiology
Volume312
Issue number3
DOIs
StatePublished - Mar 1 2017

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Nude Rats
Interleukin-17
Neutrophil Infiltration
Natural Killer Cells
Reperfusion
Fibrosis
Ischemia
Acute Kidney Injury
T-Lymphocytes
Kidney
Mycophenolic Acid
Chronic Renal Insufficiency
Th17 Cells
Losartan
Nephrectomy
Disease Progression
Sodium
Cytokines
Diet

Keywords

  • Lymphocytes
  • Progression

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion : Compensatory role of natural killer cells in athymic rats. / Mehrotra, Purvi; Collett, Jason A.; McKinney, Seth D.; Stevens, Jackson; Ivancic, Carlie M.; Basile, David.

In: American Journal of Physiology - Renal Physiology, Vol. 312, No. 3, 01.03.2017, p. F385-F397.

Research output: Contribution to journalArticle

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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 at day 33 and 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.",
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