Abstract
The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.
Highlights
Acute kidney injury (AKI) is a commonly encountered clinical entity with significant acute morbidity and mortality [1,2,3,4,5,6]
Several studies have substantiated that activation of toll-like receptor 4 (TLR4) signaling promotes acute injury in ischemic acute kidney injury (AKI) [13,14,16,33]
Our findings in this study further validate the importance of TLR4 signaling in ischemic AKI
Summary
Acute kidney injury (AKI) is a commonly encountered clinical entity with significant acute morbidity and mortality [1,2,3,4,5,6]. In addition to the acute consequences associated with an episode of AKI, there is growing evidence that maladaptive repair following AKI ushers in the development of chronic kidney disease (CKD) in patients that survive an episode of AKI [7,8,9,10]. InRheibceitnitoninvoefsTtigLaRti4onssighnaavleinsgugmgeitsitgedatethsathtehefibrorloetiocfrTesLpRo4nascetivinatimonouesxetenmdosdbeelysoonfdfothleic acid nephraocputaethpyh,a5se/6ofthinnjuerpyhirnevcatorimouys wmiotdheclsoonfckoimdniteayndtisceoanstei.nIundoeuesda, TnLgRio4tehnassibneeinnfiumspiolinca, taenddinutnhielateral uretermalodoublsattriuonctoiof nkid[1n7e–y2f0ib].rosis and the development of chronic kidney disease (CKD) following acute. Isnigconnatlriansgt, tmhiasyachuatevperdotiescptiaornatdeidonuottcomes depentrdainnsglaoten itnhteo indiitmiailninshjuedriofuibsroesviesnsti.x weeks after injury despite a significant protection of microvascular rarefaction. These studies suggest that the role of TLR4 signaling may have disparate. Fu2.nRcteisounlatsl Deletion of TLR4 Confers Acute Protection in a Model of Ischemic AKI.
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