Transcriptional modulation of the T helper 17/interleukin 17 axis ameliorates renal ischemia-reperfusion injury.

Lee, JW ; Bae, E ; et al.

In: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal, Jg. 34 (2019-09-01), Heft 9, S. 1481-1498

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Background: Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor critical for T-cell function. Although inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway has been reported to be protective against ischemia-reperfusion injury (IRI), the role of T cell-associated STAT3 in the pathogenesis of renal IRI has not been specifically defined.

Methods: We induced renal IRI in both mice with T cell-specific STAT3 knockout (Lck-Cre;STAT3flox/flox) and wild-type controls (C57BL/6) and assessed renal damage and inflammation at 48 h after IRI. Human proximal tubular epithelial cells grown under hypoxia were treated with a JAK2 inhibitor, caffeic acid 3,4-dihydroxy-phenylethyl ester, to determine the effect of JAK2/STAT3 inhibition on renal epithelia. Independently, we disrupted Cln 3-requiring 9 (Ctr9) to inhibit T helper 17 (Th17) activation via RNA interference and determined if Ctr9 inhibition aggravates renal injury through upregulated Th17 activation.

Results: The Lck-Cre;STAT3flox/flox mice exhibited significantly reduced kidney damage compared with controls. This protective effect was associated with reduced intrarenal Th17 infiltration and proinflammatory cytokines. Human proximal tubular epithelial cells under hypoxia exhibited significant upregulation of interleukin 17 receptors, and pharmacologic inhibition of JAK2 significantly ameliorated this change. RNA interference with Ctr9 in splenocytes enhanced differentiation into Th17 cells. In vivo knockdown of Ctr9 in mice with renal IRI further aggravated Th17-associated inflammation and kidney injury.

Conclusions: STAT3 in T cells contributes to renal IRI through Th17 activation. Inhibition of Ctr9 further enhances Th17 activation and aggravates kidney injury, further supporting the role of Th17 cells in renal IRI.

Titel:	Transcriptional modulation of the T helper 17/interleukin 17 axis ameliorates renal ischemia-reperfusion injury.
Autor/in / Beteiligte Person:	Lee, JW ; Bae, E ; Kwon, SH ; Yu, MY ; Cha, RH ; Lee, H ; Kim, DK ; Lee, JP ; Ye, SK ; Yoo, JY ; Park, DJ ; Kim, YS ; Yang, SH
Link:	Full Text Finder (Volltext)
Zeitschrift:	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal, Jg. 34 (2019-09-01), Heft 9, S. 1481-1498
Veröffentlichung:	Oxford : Oxford University Press ; <i>Original Publication</i>: [Berlin ; New York, NY] : Springer International, [c1986-, 2019
Medientyp:	academicJournal
ISSN:	1460-2385 (electronic)
DOI:	10.1093/ndt/gfy370
Schlagwort:	Animals Cytokines metabolism Humans Inflammation immunology Inflammation metabolism Inflammation pathology Interleukin-17 metabolism Janus Kinase 2 genetics Janus Kinase 2 metabolism Janus Kinase 3 genetics Janus Kinase 3 metabolism Kidney metabolism Kidney pathology Mice Mice, Inbred C57BL Reperfusion Injury immunology Reperfusion Injury metabolism Reperfusion Injury pathology STAT3 Transcription Factor genetics STAT3 Transcription Factor metabolism Th17 Cells metabolism Th17 Cells pathology Gene Expression Regulation Inflammation prevention & control Interleukin-17 genetics Kidney immunology Reperfusion Injury prevention & control Th17 Cells immunology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nephrol Dial Transplant] 2019 Sep 01; Vol. 34 (9), pp. 1481-1498. MeSH Terms: Gene Expression Regulation* ; Inflammation / prevention & control ; Interleukin-17 / genetics ; Kidney / immunology ; Reperfusion Injury / prevention & control ; Th17 Cells / *immunology ; Animals ; Cytokines / metabolism ; Humans ; Inflammation / immunology ; Inflammation / metabolism ; Inflammation / pathology ; Interleukin-17 / metabolism ; Janus Kinase 2 / genetics ; Janus Kinase 2 / metabolism ; Janus Kinase 3 / genetics ; Janus Kinase 3 / metabolism ; Kidney / metabolism ; Kidney / pathology ; Mice ; Mice, Inbred C57BL ; Reperfusion Injury / immunology ; Reperfusion Injury / metabolism ; Reperfusion Injury / pathology ; STAT3 Transcription Factor / genetics ; STAT3 Transcription Factor / metabolism ; Th17 Cells / metabolism ; Th17 Cells / pathology Contributed Indexing: Keywords: Ctr9; STAT3; Th17 cells; acute kidney injury; ischemia-reperfusion injury Substance Nomenclature: 0 (Cytokines) ; 0 (Interleukin-17) ; 0 (STAT3 Transcription Factor) ; 0 (STAT3 protein, human) ; EC 2.7.10.2 (JAK2 protein, human) ; EC 2.7.10.2 (JAK3 protein, human) ; EC 2.7.10.2 (Janus Kinase 2) ; EC 2.7.10.2 (Janus Kinase 3) Entry Date(s): Date Created: 20181214 Date Completed: 20200325 Latest Revision: 20200325 Update Code: 20240513

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