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Int. J. Mol. Sci. 2016, 17(5), 647; doi:10.3390/ijms17050647

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

1
Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2
Department of Medicine, Division of Nephrology, Indiana University School of Medicine, R2-202, 950 West Walnut Street, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Alan Parrish
Received: 30 March 2016 / Revised: 19 April 2016 / Accepted: 25 April 2016 / Published: 29 April 2016
(This article belongs to the Special Issue Advances in Chronic Kidney Disease)
View Full-Text   |   Download PDF [5873 KB, uploaded 29 April 2016]   |  

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. View Full-Text
Keywords: toll-like receptor 4; acute kidney injury; ischemia-reperfusion; fibrosis toll-like receptor 4; acute kidney injury; ischemia-reperfusion; fibrosis
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MDPI and ACS Style

Dagher, P.C.; Hato, T.; Mang, H.E.; Plotkin, Z.; Richardson, Q.V.; Massad, M.; Mai, E.; Kuehl, S.E.; Graham, P.; Kumar, R.; Sutton, T.A. Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury. Int. J. Mol. Sci. 2016, 17, 647.

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