The pendrin anion exchanger gene is transcriptionally regulated by uroguanylin: a novel enterorenal link

Rozenfeld, Julia; Tal, Osnat; Kladnitsky, Orly; Adler, Lior; Efrati, Edna; Carrithers, Stephen L.; Alper, Seth L.; Zelikovic, Israel

doi:10.1152/ajprenal.00189.2011

Cited by 21 publications

(26 citation statements)

References 59 publications

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“…Furthermore, it is demonstrated that multiple plasma membrane transporters, such as SLC26a6 and NBCe1 (a basolateral Na ϩ /HCO 3 Ϫ -contransporter), in addition to apical CFTR or NKCC1, may be acted on by the guanylin peptides, based on the observed inhibition of HCO 3 Ϫ secretion. Indeed, a recent study revealed that UGN injected into mice resulted in decreased mRNA and protein expression of renal pendrin/SLC26a4, another Na ϩ / HCO 3 Ϫ cotransporter (51). Future studies should examine if the guanylin peptides affect the activity of SLC26a6 and NBCe1.…”

Section: Perspectives and Significancementioning

confidence: 98%

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

Ruhr

Bodinier

Mager

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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The physiological effects of guanylin (GN) and uroguanylin (UGN) on fluid and electrolyte transport in the teleost fish intestine have yet to be thoroughly investigated. In the present study, the effects of GN, UGN, and renoguanylin (RGN; a GN and UGN homolog) on short-circuit current ( Isc) and the transport of Cl−, Na+, bicarbonate (HCO3−), and fluid in the Gulf toadfish ( Opsanus beta) intestine were determined using Ussing chambers, pH-stat titration, and intestinal sac experiments. GN, UGN, and RGN reversed the Isc of the posterior intestine (absorptive-to-secretory), but not of the anterior intestine. RGN decreased baseline HCO3− secretion, but increased Cl− and fluid secretion in the posterior intestine. The secretory response of the posterior intestine coincides with the presence of basolateral NKCC1 and apical cystic fibrosis transmembrane conductance regulator (CFTR), the latter of which is lacking in the anterior intestine and is not permeable to HCO3− in the posterior intestine. However, the response to RGN by the posterior intestine is counterintuitive given the known role of the marine teleost intestine as a salt- and water-absorbing organ. These data demonstrate that marine teleosts possess a tissue-specific secretory response, apparently associated with seawater adaptation, the exact role of which remains to be determined.

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Section: Perspectives and Significancementioning

confidence: 98%

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

Ruhr

Bodinier

Mager

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…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.…”

Section: Discussionmentioning

confidence: 96%

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

Vanoni

Nofziger²,

Dossena³

et al. 2013

Cell Physiol Biochem

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Background: Pendrin, an anion exchanger associated with the inner ear, thyroid and kidney, plays a significant role in respiratory tissues and diseases, where its expression is increased following IL-4 and IL-13 exposure. The mechanism leading to increased pendrin expression is in part due to binding of STAT6 to a consensus sequence (N₄ GAS motif) located in the pendrin promoter. As retrospective analyses of the 5' upstream sequence of the human pendrin promoter revealed an additional N₄ GAS motif (1660 base pairs upstream of the one previously identified), we set out to define its contribution to IL-4 stimulated changes in pendrin promoter activity. Methods and Results: Electrophoretic mobility shift assays showed that STAT6 bound to oligonucleotides corresponding to both N₄ GAS motifs in vitro, while dual luciferase promoter assays revealed that only one of the N₄ GAS motifs was necessary for IL-4 -stimulated increases in pendrin promoter activity in living cells. We then examined the ability of STAT6 to bind each of the N₄ GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N₄ GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment. Conclusions: Of the two N₄ GAS motifs located in the human pendrin promoter region analyzed in this study (nucleotides -3906 to +7), only the one located nearest to the first coding ATG participates in IL-4 stimulated increases in promoter activity.

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“…Considering the major role of both guanylin peptides and pendrin in the regulation of total body NaCl content, maintenance of extracellular fluid volume and control of blood pressure, we investigated UGN modulation of pendrin expression and explored the molecular mechanisms responsible for this modulation [81]. …”

Section: The Anion Exchanger Pendrinmentioning

confidence: 99%

“…UGN also decreased endogenous pendrin mRNA levels in HEK293 cells [81]. We next examined possible modulation by UGN of human PDS ( hPDS ) transcription at the level of the hPDS promoter [81]. …”

Section: The Anion Exchanger Pendrinmentioning

confidence: 99%

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

Rozenfeld

Tal

Kladnitsky

et al. 2013

Cell Physiol Biochem

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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.

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The pendrin anion exchanger gene is transcriptionally regulated by uroguanylin: a novel enterorenal link

Cited by 21 publications

References 59 publications

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

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

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

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The pendrin anion exchanger gene is transcriptionally regulated by uroguanylin: a novel enterorenal link

Cited by 21 publications

References 59 publications

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine

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

Pendrin, a Novel Transcriptional Target of the Uroguanylin System

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