An emerging role of pendrin in health and disease

The pendrin gene (SLC26A4) was initially identified through the positional cloning in patients with Pendred syndrome, a heritable recessive genetic disorder (MIM #274600) characterized by deafness and goiter (Everett et al. 1997). Pendrin encodes for a transmembrane electroneutral exchanger for monovalent anions (e.g. I , formate, HCO3 , and Cl ). As predicted from the linkage between pendrin gene and characteristics of Pendred’s syndrome, pendrin is highly expressed in the inner ear and thyroid gland, where it controls the volume and pH of the endolymphatic fluid, and the transport of iodide required for organification of thyroid hormones, respectively. Pendrin is also highly expressed in the kidney where it controls the final excretion of bicarbonate (Royaux et al. 2001) and NaCl reabsorption and overall blood pressure (Eladari et al. 2014). Although physiological roles of pendrin have been most extensively investigated in the three organs discussed above, pendrin is also expressed in airway epithelia, mammary gland and liver (Wangemann 2013). In these different organs, the function of pendrin is still unknown. However, there is an emerging interest in the relevance of pendrin in airway surface epithelia, because several studies show a possible association of pendrin with asthma. For example, Nakao et al. (Nakao et al. 2008) demonstrated that forced expression of pendrin in human carcinogenic cell line (NCI-H292) and mouse lung significantly increased expression of mucin (Muc5ac), a component of the mucus. In addition to these changes, pendrin overexpression led to elevated airway hyper-reactivity. Furthermore, Nakagami et al. (Nakagami et al. 2008) also showed that although there was no significant difference under the baseline condition between wild-type and pendrin knockout mice, inflammation and airway hyper-reactivity induced by ovalbumin injection were significantly alleviated in pendrin knockout mice. While the results from mouse models suggest that abnormal overexpression of pendrin in airway epithelia could lead to severe airway inflammation, for clinical purposes it is imperative to test the role of pendrin in airway epithelia directly using human tissue. To address this point, the present study by Lee et al. (Lee et al. in press) utilized primary cell culture established from human nasal epithelial cells collected from either human subjects harboring bi-allelic inactivating mutations in pendrin or subjects with functional pendrin proteins. They treated these two primary cultures with a TH2-type cytokine (IL-13), one of the key mediators in inflammatory response in asthma, and analyzed the ASL thickness, expression and activities of selected ion transporters expressed on human nasal epithelia, as well as status of goblet cells, a specialized mucus-secreting cells. Because nasal epithelia express a variety of transporters, one important question is to determine the relative role of pendrin in electrolyte transport in these cells. At mRNA level, Lee et al. detected 9 anion exchangers in addition to pendrin. Among those genes, only SLC26A3 was significantly elevated in response to IL-13 treatment, and the magnitude of increase was much lower than that of pendrin (roughly 10 and 100-fold increase for SLC26A3 and pendrin, respectively). Furthermore, following the IL-13 treatment, no increase in Cl -dependent HCO3 transport activity was observed in the pendrinnull cell culture. In addition to the anion exchangers, they also compared the mRNA expression and activity level of epithelial Na channel (ENaC), ANO-1 (Ca-dependent Cl channel) and cystic fibrosis transmembrane conductance regulator (CFTR) between the two cultures under the baseline condition. The only significant difference observed in this study was reduction in mRNA expression of CFTR in the pendrin-null cell culture. Overall, pendrin is likely to be the major mediator of Cl -HCO3 exchange activity in nasal epithelia following IL-13 treatment, but at the same time, the loss of pendrin had very little effect on the expression of other transporters. On the other hand, the loss of pendrin led to major physiological changes in nasal epithelia. Unlike results from mouse models, the ASL was significantly thicker in pendrin-null cell culture even in the baseline condition,