title: 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.
authors.affiliation: Laboratory of Developmental Nephrology, Department of Physiology and Biophysics, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Rozenfeld
authors.forename: Osnat
authors.initials: O
authors.lastname: Tal
authors.forename: Orly
authors.initials: O
authors.lastname: Kladnitsky
authors.forename: Lior
authors.initials: L
authors.lastname: Adler
authors.forename: Edna
authors.initials: E
authors.lastname: Efrati
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Carrithers
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Israel
authors.initials: I
authors.lastname: Zelikovic
mesh_terms: D006152:Cyclic GMP / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D045265:Natriuretic Peptides / Q000378:metabolism*; D015398:Signal Transduction; D000076988:Sulfate Transporters; D014158:Transcription, Genetic
chemical_list: D005768:Gastrointestinal Hormones; D026901:Membrane Transport Proteins; D045265:Natriuretic Peptides; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; C072685:guanylin; C084362:uroguanylin; D006162:Guanylate Cyclase; D006152:Cyclic GMP