title: Lymphocyte-specific deletion of IKK2 or NEMO mediates an increase in intrarenal Th17 cells and accelerates renal damage in an ischemia-reperfusion injury mouse model.
abstract: Acute kidney injury (AKI) is associated with poor patient outcome and a global burden for end-stage renal disease. Ischemia-reperfusion injury (IRI) is one of the major causes of AKI, and experimental work has revealed many details of the inflammatory response in the kidney, such as activation of the NF-κB pathway. Here, we investigated whether deletion of the NF-κB kinases IKK2 or NEMO in lymphocytes or systemic inhibition of IKK2 would cause different kidney inflammatory responses after IRI induction. Serum creatinine, blood urea nitrogen (BUN) level, and renal tubular injury score were significantly increased in CD4creIKK2f/f(CD4xIKK2Δ) and CD4creNEMOf/f(CD4xNEMOΔ) mice compared with CD4cre mice after IRI induction. The frequency of Th17 cells infiltrating the kidneys of CD4xIKK2Δor CD4xNEMOΔmice was also significantly increased at all time points. CCL20, an important chemokine in Th17 cell recruitment, was significantly increased at early time points after the induction of IRI. IL-1β, TNF-α, and CCL2 were also significantly increased in different patterns. A specific IKK2 inhibitor, KINK-1, reduced BUN and serum creatinine compared with nontreated mice after IRI induction, but the frequency of kidney Th17 cells was also significantly increased. In conclusion, although systemic IKK2 inhibition improved kidney function, lymphocyte-specific deletion of IKK2 or NEMO aggravated kidney injury after IRI, and, in both conditions, the percentage of Th17 cells was increased. Our findings demonstrate the critical role of the NF-κB pathway in Th17 activation, which advises caution when using systemic IKK2 inhibitors in patients with kidney injury, since they might impair the T cell response and aggravate renal disease.
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors: Linlin
authors: L
authors: Guo
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors: Hannah Heejung
authors: HH
authors: Lee
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors: María de Las Mercedes
authors: ML
authors: Noriega
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors: Hans J
authors: HJ
authors: Paust
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors: Gunther
authors: G
authors: Zahner
authors: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany thaiss@uke.de.
authors: Friedrich
authors: F
authors: Thaiss
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D054418:Chemokine CCL20 / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010078:Oxazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: C502972:7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one; D054418:Chemokine CCL20; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D010078:Oxazines; D011725:Pyridines; D003404:Creatinine; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: IκB kinase; Th17 cells; ischemia-reperfusion injury; nuclear factor-κB essential modulator; nuclear factor-κB transcription factor; signalosome complex