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

TY - JOUR

T1 - 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

AU - Guo, Linlin

AU - Lee, Hannah Heejung

AU - Noriega, María de Las Mercedes

AU - Paust, Hans J

AU - Zahner, Gunther

AU - Thaiss, Friedrich

N1 - Copyright © 2016 the American Physiological Society.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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 CD4xIKK2Δ or CD4xNEMOΔ mice 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.

AB - 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 CD4xIKK2Δ or CD4xNEMOΔ mice 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.

KW - Animals

KW - Blood Urea Nitrogen

KW - Chemokine CCL20

KW - Creatinine

KW - Disease Models, Animal

KW - I-kappa B Kinase

KW - Intracellular Signaling Peptides and Proteins

KW - Kidney

KW - Lymphocytes

KW - Mice

KW - Mice, Knockout

KW - Oxazines

KW - Pyridines

KW - Reperfusion Injury

KW - Th17 Cells

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1152/ajprenal.00242.2016

DO - 10.1152/ajprenal.00242.2016

M3 - SCORING: Journal article

C2 - 27582100

VL - 311

SP - F1005-F1014

JO - AM J PHYSIOL-RENAL

JF - AM J PHYSIOL-RENAL

SN - 1931-857X

IS - 5

ER -