Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance

Abstract

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.

Osteopontin deficiency aggravates hepatic injury induced by ischemia–reperfusion in mice

“…18 The overexpression of OPN via the hyperactivation of Wnt signaling, as detected in Brown Norway rats, is also critical for the maintenance of their inherent ischemic resistance. 20 However, OPN again stimulated the development of renal fibrosis after acute ischemic insult. 19 …”

“…OPN reduces mitochondrial cytochrome c release and caspase 3 activity after renal I–R. 20 It has also been reported that OPN expressed in tubular epithelial cells regulates NK cell-mediated kidney I–R injury. 21 …”

Revealing the Underlying Mechanism of Ischemia Reperfusion Injury Using Bioinformatics Approach

“…The data GSE9943 [13] were downloaded from the National Center for Biotechnology Information (NCBI) Genome Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) database [14]. Totally 12 samples were available within the data, including two groups (I/R group and control group) for both Brown Norway (BN) and Sprague Dawley (SD) rats (n = 3 per group).…”

Wnt Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia-Reperfusion

“…It was previously recognized that Brown Norway rats are particularly resistant to renal IR due to congenital increased in Wnt/β-catenin signaling relative to other species of rats (33). In another study, transfection with a vector coding for the Wnt1 ligand protected human kidney cells from apoptosis after exposure to staurosporin (7).…”