Role of AE2 for pH(i) regulation in biliary epithelial cells

The Cl(−)/HCO(−)(3)anion exchanger 2 (AE2) is known to be involved in intracellular pH (pH(i)) 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 pH(i) regulation in cholangiocytes from normal and Ae2(−/−)(a,b) mice confirmed that AE2 is the transporter responsible for the Cl(−)/HCO(−)(3)exchange 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 pH(i) regulation in the absence of AE2.