Transcriptional Regulation of the Pendrin Gene

Abstract

Pendrin (SLC26A4), a Cl^-/anion exchanger encoded by the gene PDS, is highly expressed in the kidney, thyroid and inner ear epithelia and is essential for bicarbonate secretion /chloride reabsorption, iodide accumulation and endolymph ion balance, respectively. The molecular mechanisms controlling pendrin activity in renal, thyroid and inner ear epithelia have been the subject of recent studies. The effects of ambient pH, the hormone aldosterone and the peptide uroguanylin (UGN; the “intestinal natriuretic hormone”), known modulators of electrolyte balance, on transcription of the pendrin gene, have been investigated. Luciferase reporter plasmids containing different length fragments of the human PDS (hPDS) promoter were transfected into renal HEK293, thyroid LA2, and inner ear VOT36 epithelial cells. Acidic pH decreased and alkaline pH increased hPDS promoter activity in transfected HEK293 and VOT36, but not in LA2 cells. Aldosterone reduced hPDS promoter activity in HEK293 but had no effect in LA2 and VOT36 cells. These pH and aldosterone-induced effects on the hPDS promoter occurred within 96-bp and 89-bp regions, respectively, which likely contain distinct response elements to these modulators. Injection of UGN into mice resulted in decreased pendrin mRNA and protein expression in the kidney. Exposure of transfected HEK293 to UGN decreased hPDS promoter activity. The findings provided evidence for the presence of a UGN response element within the 96-bp region overlapping with the pH response element on the hPDSpromoter. Pendrin is also expressed in airway epithelium. The cytokins interleukin 4 (IL-4) and interleukin-13 (IL-13), known regulators of airway surface function, have been shown to increase hPDS promoter activity by a STAT6-dependent mechanism. In conclusion, systemic pH, the hormone aldosterone, and the peptide UGN influence renal tubular pendrin gene expression and, perhaps, pendrin-mediated Cl^-/HCO₃^- exchange at the transcriptional level. Pendrin-driven anion transport in the endolymph and at the airway surface may be regulated transcriptionally by systemic pH and IL-3/IL-4, respectively. The distinct response elements and the corresponding transcription factors mediating the effect of these modulators on the PDS promoter remain to be identified and characterized.

The Human Pendrin Promoter Contains two N4GAS Motifs with Different Functional Relevance

“…Of these 5 protein coding transcripts, only the one (Ensemble transcript ID# ENST00000265715) encoding a 780 amino acid long protein (from 21 exons) was originally linked to Pendred Syndrome [4]. Since then, the promoter controlling this particular open reading frame has been the subject of many investigations [18,23,30,31,32,33,34,35,36,37,38], as well as the present study.…”

The ESF Meeting on „The Proteomics, Epigenetics and Pharmacogenetics of Pendrin“

“…This finding could explain pendrin upregulation observed in murine asthma models, an event linked to asthma and COPD exacerbations [54,62].…”

“…This knowledge could aid in the development of new pharmacological leads for asthma, COPD and/or hypertension therapy. The main findings regarding pendrin transcriptional regulation are reviewed by Rozenfeld et al in this Special Issue [62]. Ambient pH and known modulators of electrolyte balance (aldosterone and the intestinal natriuretic hormone UGN) modulate human pendrin promoter activity by acting on distinct response elements.…”

Synopsis of the 48thAnnual Meeting of the Lake Cumberland Biological Transport Group and the Second Biannual Meeting of the Pendrin Consortium

“…Acidic pH decreases and alkaline pH increases pendrin promoter activity in kidney and inner ear epithelial cell lines, but not in thyroid cells. Aldosterone reduces pendrin promoter activity in kidney, but has no effect in thyroid and inner ear cells [76]. …”