title: Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury.
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.
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. pdaghe2@iu.edu.
authors.forename: Pierre C
authors.initials: PC
authors.lastname: Dagher
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. thato@iu.edu.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hato
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. hmang@iu.edu.
authors.forename: Henry E
authors.initials: HE
authors.lastname: Mang
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. zplotkin@iu.edu.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Plotkin
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. qrichardson991@gmail.com.
authors.forename: Quentin V
authors.initials: QV
authors.lastname: Richardson
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. michaelpmassad@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Massad
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Erik.m.mai@gmail.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Mai
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. kuehly@mac.com.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Kuehl
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. grahamp@purdue.edu.
authors.forename: Paige
authors.initials: P
authors.lastname: Graham
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. kumaryd@gmail.com.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Division of Nephrology, Indiana University School of Medicine, R2-202, 950 West Walnut Street, Indianapolis, IN 46202, USA. tsutton2@iu.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Sutton
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000294:innervation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051197:Toll-Like Receptor 4; D003404:Creatinine
keywords: acute kidney injury; fibrosis; ischemia-reperfusion; toll-like receptor 4