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2016 ; 27
(9
): 2658-69
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Tubular Epithelial NF-?B Activity Regulates Ischemic AKI
#MMPMID26823548
Markó L
; Vigolo E
; Hinze C
; Park JK
; Roël G
; Balogh A
; Choi M
; Wübken A
; Cording J
; Blasig IE
; Luft FC
; Scheidereit C
; Schmidt-Ott KM
; Schmidt-Ullrich R
; Müller DN
J Am Soc Nephrol
2016[Sep]; 27
(9
): 2658-69
PMID26823548
show ga
NF-?B is a key regulator of innate and adaptive immunity and is implicated in the
pathogenesis of AKI. The cell type-specific functions of NF-?B in the kidney are
unknown; however, the pathway serves distinct functions in immune and tissue
parenchymal cells. We analyzed tubular epithelial-specific NF-?B signaling in a
mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-?B reporter
activity and nuclear localization of phosphorylated NF-?B subunit p65 analyses in
mice revealed that IRI induced widespread NF-?B activation in renal tubular
epithelia and in interstitial cells that peaked 2-3 days after injury. To
genetically antagonize tubular epithelial NF-?B activity, we generated mice
expressing the human NF-?B super-repressor I?B??N in renal proximal, distal, and
collecting duct epithelial cells. Compared with control mice, these mice
exhibited improved renal function, reduced tubular apoptosis, and attenuated
neutrophil and macrophage infiltration after IRI-induced AKI. Furthermore,
tubular NF-?B-dependent gene expression profiles revealed temporally distinct
functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary
proximal tubular cells isolated from I?B??N-expressing mice and exposed to
hypoxia-mimetic agent cobalt chloride exhibited less apoptosis and expressed
lower levels of chemokines than cells from control mice did. Our results indicate
that postischemic NF-?B activation in renal tubular epithelia aggravates tubular
injury and exacerbates a maladaptive inflammatory response.