Pendrin, a Novel Transcriptional Target of the Uroguanylin System

Abstract

Guanylin (GN) and uroguanylin (UGN) are low-molecular-weight peptide hormones produced mainly in the intestinal mucosa in response to oral salt load. GN and UGN (guanylin peptides) induce secretion of electrolytes and water in both intestine and kidney. Thought to act as “intestinal natriuretic factors”, GN and UGN modulate renal salt secretion by both endocrine mechanisms (linking the digestive system and kidney) and paracrine/autocrine (intrarenal) mechanisms. The cellular function of GN and UGN in intestine and proximal tubule is mediated by guanylyl cyclase C (GC-C)-, cGMP-, and G protein-dependent pathways, whereas, in principal cells of the cortical collecting duct (CCD), these peptide hormones act via GC-C-independent signaling through phospholipase A₂ (PLA₂). The Cl^-/HCO^-₃ exchanger pendrin (SLC26A4), encoded by the PDS gene, is expressed in non-α intercalated cells of the CCD. Pendrin is essential for CCD bicarbonate secretion and is also involved in NaCl balance and blood pressure regulation. Our recent studies have provided evidence that pendrin-mediated anion exchange in the CCD is regulated at the transcriptional level by UGN. UGN exerts an inhibitory effect on the pendrin gene promoter likely via heat shock factor 1 (HSF1) action at a defined heat shock element (HSE) site. Recent studies have unraveled novel roles for guanylin peptides in several organ systems including involvement in appetite regulation, olfactory function, cell proliferation and differentiation, inflammation, and reproductive function. Both the guanylin system and pendrin have also been implicated in airway function. Future molecular research into the receptors and signal transduction pathways involved in the action of guanylin peptides and the pendrin anion exchanger in the kidney and other organs, and into the links between them, may facilitate discovery of new therapies for hypertension, heart failure, hepatic failure and other fluid retention syndromes, as well as for diverse diseases such as obesity, asthma, and cancer.

Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease

“…Surprisingly, the prevalence of PDS-aAb was only slightly higher in thyroid patients than in controls, indicating that AITD may not be the relevant disease for autoimmunity to PDS. Studies in other diseases potentially related to PDS expression are needed next to elucidate a possible role of PDS-aAb in conditions other than AITD, like diseases of the lungs (28), esophagus (29), placenta (30), kidney (31) or in rhinosinusitis (32).…”

High Salt Intake Promotes Different Responses to Urodilatin and Uroguanylin in the Isolated Rat Kidney

“…This sensitivity was associated with a rise in cGMP levels in urine and an upregulation of the GC-C receptor and downregulation of guanylate cyclase A (GC-A) receptors in kidney seen by real time PCR [15]. The guanylin family signaling pathways in the kidney has become the subject of numerous recent research due to its great importance in this process [7,15,28,39]. Therefore, the current study demonstrates that uroguanylin is more important than urodilatin in excreting sodium after a chronic salt overload diet.…”

Novel Roles for Chloride Channels, Exchangers, and Regulators in Chronic Inflammatory Airway Diseases

“…In the inner ear, pendrin helps maintain Cl − and HCO 3 − homeostasis, which is crucial for normal hearing and for the development of bony structures such as the cochlea and the vestibular aqueduct [ 71 ]. In the thyroid gland, pendrin contributes I − to the follicle for thyroxine biosynthesis [ 72 ], and in the cortical collecting duct the transporter is implicated in Cl − reabsorption through functional coupling with the epithelial Na + channel ENaC and the Na + -dependent Cl − /HCO 3 − exchanger NDCBE/SLC4A8 [ 73 ]. Most interestingly, it has been shown that in the bronchial epithelium pendrin mediates an increase in Cl − /SCN − exchange in response to IL-4 stimulation [ 74 ] to provide SCN − substrate to lactoperoxidase for the synthesis of hypothiocyanite (OSCN − ), a molecule with antimicrobial properties [ 75 ], and this underscores the emerging role of pendrin in innate airway defense mechanisms ( Figure 5 ).…”