502 Increased Folate Transport During Folate Deficiency Is Associated with Upregulation of Reduced Folate Carrier and Proton Coupled Folate Transporter in Rat Intestine

Abstract

G A A b st ra ct s HIF-1α signaling in response to Cdif toxin. Results: Caco-2 cells exposed to Cdif toxin displayed a significant increase in HIF-1α transcription, protein levels and DNA binding. Cdif toxin-induced HIF-1α protein accumulation was attenuated by nitric oxide synthase inhibitors. Loss of HIF-1α increased Cdif toxin-induced injury In Vitro and resulted in impaired barrier function and wound repair. In Vivo, loss of HIF-1α resulted in markedly more severe intestinal injury and inflammation as assessed by histological scoring, tissue MPO levels and serum nitric oxide levels. Up-regulation of HIF-1α, with a HIF-1α-stabilizing agent, significantly reduced Cdif toxin-induced injury and inflammation. The mechanisms involved in these HIF-1α-mediated protective events involved enhanced expression of VEGFa, CD73 and intestinal trefoil factor and down-regulation of proinflammatory molecules TNF and KC. Conclusions: Our studies are the first to describe that HIF-1α plays an innate protective role in CDAD and that Cdif toxin can directly enhance HIF-1α activity. Harnessing the innate protective actions of HIF-1α in response to Cdif may represent a novel form of therapy for CDAD.