Pradeep K Dudeja, Ph.D.
Department of Medicine
University of Illinois at Chicago & Jesse Brown VAMC
Impaired absorption of electrolytes is a hallmark of diarrhea associated with inflammation or enteric infections. Intestinal epithelial luminal membrane NHE3 (Na+/H+ exchanger 3) and SLC26A3 or DRA (Down Regulated in Adenoma, a Cl-/HCO3- exchanger, which is mutated in congenital chloride diarrhea patients) play key roles in mediating electroneutral NaCl absorption. Our recent studies have shown a marked decrease in function and expression of DRA (SLC26A3) in mouse models of enteropathogenic infections and in models of gut inflammation. In addition, our in vitro studies have demonstrated direct down-regulation of DRA expression in response to cytokines, miRNA and NFkB via transcriptional and post-transcriptional mechanisms. Hence, SLC26A3 has emerged as a novel therapeutic target for diarrheal diseases. Therefore, strategies to upregulate SLC26A3 function or expression are considered to have beneficial effects in diarrheal diseases. Our group has performed extensive studies to demonstrate potential beneficial roles of probiotics, lysophosphatidic acid and all trans retinoic acid (ATRA) in upregulation of this transporter. In this talk, evidence will be presented to show the critical role of SLC26A3 (DRA) in diarrheal diseases and the stimulatory effects of probiotics and ATRA in upregulating its function/expression. Targeting this critical chloride transporter is a novel strategy for developing therapies for diarrheal diseases.
(Supported by NIDDK and Dept. of Veterans Affairs).