Role of AE2 for pHi regulation in biliary epithelial cells.
The Cl(-)/HCO(-) 3anion exchanger 2 (AE2) is known to be involved in intracellular pH (pHi) regulation and transepithelial acid-base transport. Early studies showed that AE2 gene expression is reduced in liver biopsies and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic non-suppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. Microfluorimetric analysis of the Cl(-)/HCO(-) 3 anion exchange (AE) in isolated cholangiocytes showed that the cAMP-stimulated AE activity is diminished in PBC compared to both healthy and diseased controls. More recently, it was found that miR-506 is upregulated in cholangiocytes of PBC patients and that AE2 may be a target of miR-506. Additional evidence for a pathogenic role of AE2 dysregulation in PBC was obtained with Ae2 (-/-) a,b mice, which develop biochemical, histological, and immunologic alterations that resemble PBC (including development of serum AMA). Analysis of HCO(-) 3 transport systems and pHi regulation in cholangiocytes from normal and Ae2 (-/-) a,b mice confirmed that AE2 is the transporter responsible for the Cl(-)/HCO(-) 3exchange in these cells. On the other hand, both Ae2 (+/+) a,b and Ae2 (-/-) a,b mouse cholangiocytes exhibited a Cl(-)-independent bicarbonate transport system, essentially a Na(+)-bicarbonate cotransport (NBC) system, which could contribute to pHi regulation in the absence of AE2.
Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), School of Medicine, University of Navarra, and Ciberehd Pamplona, Spain.
Axel R
AR
Concepcion
Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), School of Medicine, University of Navarra, and Ciberehd Pamplona, Spain.
María
M
Lopez
Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), School of Medicine, University of Navarra, and Ciberehd Pamplona, Spain.
Alberto
A
Ardura-Fabregat
Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), School of Medicine, University of Navarra, and Ciberehd Pamplona, Spain.
Juan F
JF
Medina
Cl−/HCO−3 anion exchange; bile flow; biliary HCO−3 secretion; cholangiocytes; primary biliary cirrhosis