title: The pendrin anion exchanger gene is transcriptionally regulated by uroguanylin: a novel enterorenal link.
abstract: The pendrin/SLC26A4 Cl(-)/HCO(3)(-) exchanger, encoded by the PDS gene, is expressed in cortical collecting duct (CCD) non-A intercalated cells. Pendrin is essential for CCD bicarbonate secretion and is also involved in NaCl balance and blood pressure regulation. The intestinal peptide uroguanylin (UGN) is produced in response to oral salt load and can function as an "intestinal natriuretic hormone." We aimed to investigate whether UGN modulates pendrin activity and to explore the molecular mechanisms responsible for this modulation. Injection of UGN into mice resulted in decreased pendrin mRNA and protein expression in the kidney. UGN decreased endogenous pendrin mRNA levels in HEK293 cells. A 4.2-kb human PDS (hPDS) promoter sequence and consecutive 5' deletion products were cloned into luciferase reporter vectors and transiently transfected into HEK293 cells. Exposure of transfected cells to UGN decreased hPDS promoter activity. This UGN-induced effect on the hPDS promoter occurred within a 52-bp region encompassing a single heat shock element (HSE). The effect of UGN on the promoter was abolished when the HSE located between nt -1119 and -1115 was absent or was mutated. Furthermore, treatment of HEK293 cells with heat shock factor 1 (HSF1) small interfering RNA (siRNA) reversed the UGN-induced decrease in endogenous PDS mRNA level. In conclusion, pendrin-mediated Cl(-)/HCO(3)(-) exchange in the renal tubule may be regulated transcriptionally by the peptide hormone UGN. UGN exerts its inhibitory activity on the hPDS promoter likely via HSF1 action at a defined HSE site. These data define a novel signaling pathway involved in the enterorenal axis controlling electrolyte and water homeostasis.
authors: Laboratory of Developmental Nephrology, Department of Physiology and Biophysics, Haifa, Israel.
authors: Julia
authors: J
authors: Rozenfeld
authors: Osnat
authors: O
authors: Tal
authors: Orly
authors: O
authors: Kladnitsky
authors: Lior
authors: L
authors: Adler
authors: Edna
authors: E
authors: Efrati
authors: Stephen L
authors: SL
authors: Carrithers
authors: Seth L
authors: SL
authors: Alper
authors: Israel
authors: I
authors: Zelikovic
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D045265:Natriuretic Peptides / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000076988:Sulfate Transporters; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D045265:Natriuretic Peptides; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D014157:Transcription Factors; C084362:uroguanylin