2261 SIGNIFICANCE AND THERAPEUTIC POTENTIAL OF TARGETING DELTA-LIKE 4 IN RENAL ISCHEMIA REPERFUSION INJURY

Abstract

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Vascular Surgery II1 Apr 20122261 SIGNIFICANCE AND THERAPEUTIC POTENTIAL OF TARGETING DELTA-LIKE 4 IN RENAL ISCHEMIA REPERFUSION INJURY Kiyohiko Hotta, Masayuki Sho, Ichiro Yamato, Hiroshi Harada, Hideo Yagita, Yoshiyuki Nakajima, and Katsuya Nonomura Kiyohiko HottaKiyohiko Hotta Sapporo, Japan More articles by this author , Masayuki ShoMasayuki Sho Kashihara, Japan More articles by this author , Ichiro YamatoIchiro Yamato Kashihara, Japan More articles by this author , Hiroshi HaradaHiroshi Harada Sapporo, Japan More articles by this author , Hideo YagitaHideo Yagita Tokyo, Japan More articles by this author , Yoshiyuki NakajimaYoshiyuki Nakajima Kashihara, Japan More articles by this author , and Katsuya NonomuraKatsuya Nonomura Sapporo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2439AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Delta-Like 4 (DL4), which is one of Notch ligands, affects many differentiation processes and cell fate determination during embryonic and postnatal development. Furthermore, it regulates tumor angiogenesis and promotes tumor growth. Recently it has been recognized as a critical regulator in lots of immune responses. However, its role in ischemia reperfusion injury (IRI) remains unknown. In this study, we investigated the role of DLL4 in IRI. METHODS IRI was induced in male C57BL/6 mice and MyD88 KO mice. The right kidney was removed, and then left renal pedicle was clamped for 30 minutes. In a lethal model, the left kidney vessels of mice were clamped for 40 minutes. To clarify the precise functions, we employed anti-DLL4 blocking mAb (HMD4-1). RESULTS The HMD4-1 treatment significantly inhibited renal IRI as determined by serum creatinine level. Histological analysis revealed that severe tubular necrosis and massive cellular infiltrations were identified in the control kidney, while there were less necrosis and cellular infiltrations in the treated kidney. Furthermore, the treatment significantly inhibited the accumulation of both neutrophils and macrophages as determined by MPO and F4/80 staining, respectively. To address the underlying mechanisms, we evaluated local immune status. Real-time PCR analysis indicated that the treatment downregulated the expressions of several potent proinflammatory cytokines, chemokines, and adhesion molecules. Moreover, apoptosis, as measured by TUNEL staining, was also significantly inhibited. Importantly, while there was a decrease in renal tubules and collagen deposition in interstitial tissue in control kidneys at 30 days after reperfusion, tubular architecture was preserved and collagen deposition was less in the treated kidneys. Thus, DLL4 blockade attenuated the development of chronic tubular fibrosis. Furthermore, DLL4 blockade significantly prolonged the survival of lethally injured mice. Taken together, DLL4 blockade inhibited local immune activation as well as cellular infiltrations, thereby resulting in the inhibition of apoptosis and preservation of renal functions. Finally, to reveal signaling pathway of DLL4 in IRI, we used MyD88 KO mice. The protection induced by DLL4 blockade was no longer observed in MyD88 KO mice, indicating that DLL4 signaling was dependent on MyD88-mediated pathway in IRI. CONCLUSIONS Our data highlight for the first time the significance of DLL4 in the pathogenesis of IRI and also clinical potential of its targeting as a novel therapeutic strategy. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e912-e913 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kiyohiko Hotta Sapporo, Japan More articles by this author Masayuki Sho Kashihara, Japan More articles by this author Ichiro Yamato Kashihara, Japan More articles by this author Hiroshi Harada Sapporo, Japan More articles by this author Hideo Yagita Tokyo, Japan More articles by this author Yoshiyuki Nakajima Kashihara, Japan More articles by this author Katsuya Nonomura Sapporo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...