Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance.
Certain determinants of ischemic resistance in the Brown Norway rat strain have been proposed, but no studies to date have focused on the role of the Wnt pathway in the ischemic resistance mechanism. We performed a comparative genomic study in Brown Norway vs. Sprague-Dawley rats. Selective manipulations of the Wnt pathway in vivo and in vitro allowed us to study whether the action of the Wnt pathway on apoptosis through the regulation of osteopontin was critical to the maintenance of inherent ischemic resistance mechanisms. The results revealed a major gene upregulation of the Wnt family in Brown Norway rats after renal ischemia-reperfusion. Manipulation of the Wnt signaling cascade by selective antibodies increased mitochondrial cytochrome c release and caspase 3 activity. The antiapoptotic role of Wnt was mediated by osteopontin, a direct Wnt target gene. Osteopontin was reduced by Wnt antibody administration in vivo, and osteopontin gene silencing in vitro significantly increased mitochondrial cytochrome c release. The overexpression of Wnt pathway genes detected in Brown Norway rats is critical in the maintenance of their inherent ischemic resistance. Activation of the Wnt signaling cascade reduces mitochondrial cytochrome c release and caspase 3 activity through the action of osteopontin.
Viñas
Jose Luis
JL
Centro de Investigaciones Biomédicas en Red de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain. jvmbam@iibb.csic.es.
Sola
Anna
A
Jung
Michaela
M
Mastora
Chrysoula
C
Vinuesa
Eugenia
E
Pi
Felip
F
Hotter
Georgina
G
D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D013045:Species Specificity; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; C506897:Spp1 protein, rat; D051153:Wnt Proteins; D053495:Osteopontin; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3