Renal ischemia/reperfusion injury: functional tissue preservation by anti-activated {beta}1 integrin therapy.
Renal ischemia/reperfusion injury (IRI) is an important cause of acute renal failure. Cellular and molecular responses of the kidney to IRI are complex and not fully understood. beta1 integrins localize to the basal surface of tubular epithelium interacting with extracellular matrix components of the basal membrane, including collagen IV. Whether preservation of tubular epithelium integrity could be a therapeutic approach for IRI was assessed. The effects of HUTS-21 mAb administration, which recognizes an activation-dependent epitope of beta1 integrins, in a rat model of IRI were investigated. Preischemic HUTS-21 administration resulted in the preservation of renal functional and histopathologic parameters. Analyses of activated beta1 integrins expression and focal adhesion kinase phosphorylation suggest that its deactivation after IRI was prevented by HUTS-21 treatment. Moreover, HUTS-21 impaired the inflammatory response in vivo, as indicated by inhibition of proinflammatory mediators and the absence of infiltrating cells. Ex vivo adhesion assays using reperfused kidneys revealed that HUTS-21 induced a significant increase of epithelial cell attachment to collagen IV. In conclusion, the data provide evidence that HUTS-21 has a protective effect in renal IRI, preventing tubular epithelial cell detachment by preserving activated beta1 integrins functions.
Molina
Ana
A
Hospital Ramón y Cajal, Departamento de Patología, Carretera de Colmenar, Km 9.1, 28034 Madrid, Spain.
Ubeda
María
M
Escribese
María M
MM
García-Bermejo
Laura
L
Sancho
David
D
Pérez de Lema
Guillermo
G
Liaño
Fernando
F
Cabañas
Carlos
C
Sánchez-Madrid
Francisco
F
Mampaso
Francisco
F
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D001707:Biopsy, Needle; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D016207:Cytokines; D019012:Integrin beta1; D012333:RNA, Messenger; D009569:Nitric Oxide