Wen Zheng

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (11)51.06 Total impact

  • Experimental Biology-2013, Boston, USA, April 20-24 2013., Boston, USA; 04/2013
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    ABSTRACT: Duodenal epithelial cells need efficient defence strategies during gastric acidity in the lumen, while colonic mucosa counteracts damage by pathogens through the build-up of a bacteria-free adherent mucus layer. HCO(3)(-) transport is considered crucial for duodenal defence against acid as well as for mucus release and expansion, but the involved transport pathways are incompletely understood. This study investigated the significance of the electroneutral Na(+)HCO(3)(-) cotransporter NBCn1 for duodenal defence against acid and colonic mucus release. NBCn1 was localised to the basolateral membrane of duodenal villous enterocytes and of colonic crypt cells with a goblet cell predominant expression. Duodenal villous enterocyte pHi was studied before and during a luminal acid load by two-photon microscopy in exteriorised, vascularly perfused, indicator (SNARF-1 AM)-loaded duodenum of isoflurane-anaesthetised, systemic acid/base controlled mice. Acid-induced HCO(3)(-) secretion was measured in vivo by single-pass perfusion and pH-stat titration. After a luminal acid load, NBCn1-deficient duodenocytes were unable to rapidly recover from intracellular acidification and could not adequately respond with a protective HCO(3)(-) secretory response. In the colon, mucus layer build-up was delayed, and a decreased thickness of the adherent mucus layer was observed, suggesting that basolateral HCO(3)(-) uptake is essential for optimal mucus release. The electroneutral Na(+)HCO(3)(-) cotransporter NBCn1 displays a differential cellular distribution in the murine intestine and is essential for HCO(3)(-)-dependent mucosal protective functions such as pHi-recovery and HCO(3)(-) secretion in the duodenum and mucus secretion in the colon.
    The Journal of Physiology 02/2013; 591(8). DOI:10.1113/jphysiol.2012.247874 · 5.04 Impact Factor
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    ABSTRACT: Duodenocyte pHi control and HCO3 − secretion protects the proximal duodenum against damage by gastric acid. The molecular details of duodenocyte pH control are not well understood. A selective duodenal expression (within the upper GI tract) has been reported for the electroneutral Na+:HCO3 − cotransporter NBCn1 (Slc4a7). We aimed to determine the role of NBCn1 and NBCe2 in duodenocyte intracellular pH regulation as well as basal and agonist-stimulated duodenal bicarbonate secretion (JHCO3 −), exploiting mouse models of genetic slc4a7 and slc4a5 disruption. Basal and forskolin (FSK)-stimulated JHCO3 − was measured by single-pass perfusion in the duodenum of slc4a7−/− and slc4a7+/+ as well as slc4a5−/− and slc4a5+/+ mice in vivo, and by pH-stat titration in isolated duodenal mucosa in vitro. Duodenocyte HCO3 − uptake rates were fluorometrically assessed after acidification of intact villi and of isolated duodenocytes. Slc4a7−/− mice displayed significantly lower basal and FSK-stimulated duodenal HCO3 − secretion than slc4a7+/+ littermates in vivo. FSK-stimulated HCO3 − secretion was significantly reduced in slc4a7−/− isolated duodenal mucosa. Na+- and HCO3 −-dependent base uptake rates were significantly decreased in slc4a7−/− compared with slc4a7+/+ villus duodenocytes when measured in intact villi. Carbonic anhydrase (CA)-mediated CO2 hydration played no apparent role as a HCO3 − supply mechanism for basal or FSK-stimulated secretion in the slc4a7+/+ duodenum, but was an important alternative HCO3 − supply mechanism in the slc4a7−/− duodenum. NBCe2 (Slc4a5) displayed markedly lower duodenal mRNA expression levels, and its disruption did not interfere with duodenal HCO3 − secretion. The electroneutral Na+:HCO3 − cotransporter NBCn1 (slc4a7) is a major duodenal HCO3 − importer that supplies HCO3 − during basal and FSK-stimulated HCO3 − secretion.
    The Journal of Physiology 05/2012; 590(Pt 14):3317-33. DOI:10.1113/jphysiol.2011.226506 · 5.04 Impact Factor
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    ABSTRACT: Brief contact of the duodenal mucosa with luminal acid elicits a long-lasting bicarbonate (HCO(3)(-)) secretory response, which is believed to be the primary protective mechanism against mucosal damage. Here, we show that cGMP-dependent protein kinase type I-knockout (cGKI(-/-)) mice are unable to respond to a physiological H(+) stimulus with a HCO(3)(-) secretory response and spontaneously develop duodenal ulcerations. Smooth muscle-selective cGKI knock-in rescued the motility disturbance but not the defective HCO(3)(-) secretion. Proton-induced HCO(3)(-) secretion was not attenuated by selective inactivation of the cGKI gene in interstitial cells of Cajal or in enterocytes, but was abolished by inactivation of cGKI in neurons (ncGKI(-/-)). cGKI was expressed in the brainstem nucleus tractus solitarius that connects the afferent with the efferent N. vagus. Accordingly, truncation of the subdiaphragmal N. vagus significantly diminished proton-induced HCO(3)(-) secretion in wild-type mice, whereas stimulation of the subdiaphragmal N. vagus elicited a similar HCO(3)(-) secretory response in cGKI(-/-), ncGKI(-/-) and wild-type mice. These findings show that protection of the duodenum from acid injury requires neuronal cGKI.
    The FASEB Journal 01/2012; 26(4):1745-54. DOI:10.1096/fj.11-200394 · 5.04 Impact Factor
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    BMC Pharmacology 08/2009; 11(Suppl 1). DOI:10.1186/1471-2210-11-S1-P69 · 1.84 Impact Factor
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    ABSTRACT: Carbonic anhydrase (CA) is strongly expressed in the duodenum and has been implicated in a variety of physiological functions including enterocyte HCO(3)(-) supply for secretion and the "sensing" of luminal acid and CO(2). Here, we report the physiological role of the intracellular CAII isoform involvement in acid-, PGE(2,) and forskolin-induced murine duodenal bicarbonate secretion (DBS) in vivo. CAII-deficient and WT littermates were studied in vivo during isoflurane anesthesia. An approximate 10-mm segment of the proximal duodenum with intact blood supply was perfused under different experimental conditions and DBS was titrated by pH immediately. Two-photon confocal microscopy using the pH-sensitive dye SNARF-1F was used to assess duodenocyte pH(i) in vivo. After correction of systemic acidosis by infusion of isotonic Na(2)CO(3), basal DBS was not significantly different in CAII-deficient mice and WT littermates. The duodenal bicarbonate secretory response to acid was almost abolished in CAII-deficient mice, but normal to forskolin- or 16,16-dimethyl PGE(2) stimulation. The complete inhibition of tissue CAs by luminal methazolamide and i.v. acetazolamide completely blocked the response to acid, but did not significantly alter the response to forskolin. While duodenocytes acidified upon luminal perfusion with acid, no significant pH(i) change occurred in CAII-deficient duodenum in vivo. The results suggest that CA II is important for duodenocyte acidification by low luminal pH and for eliciting the acid-mediated HCO(3)(-) secretory response, but is not important in the generation of the secreted HCO(3)(-) ions.
    Proceedings of the National Academy of Sciences 08/2009; 106(31):13094-9. DOI:10.1073/pnas.0901488106 · 9.67 Impact Factor
  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)60556-4 · 16.72 Impact Factor
  • Experimental Biology meeting 2009. New Orleans, USA, 18-22 April, 2009; 04/2009
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    ABSTRACT: Knockout mouse models have provided key insights into the physiological significance of many intestinal electrolyte transporters. This review has selected three examples to highlight the importance of knockout mouse technology in unravelling complex regulatory relationships important for the understanding of human diseases. Genetic ablation of the cystic fibrosis transmembrane conductance regulator (CFTR) has created one of the most useful mouse models for understanding intestinal transport. Recent work has provided an understanding of the key role of the CFTR anion channel in the regulation of HCO3− secretion, and the important consequences that a defect in HCO3− output may have on the viscoelastic properties of mucus, on lipid absorption and on male and female reproductive function. The regulation of CFTR activity, and also that of the intestinal salt absorptive transporter NHE3, occurs via the formation of PSD95-Drosophila homologue Discs-large-tight junction protein ZO-1 (PDZ) adaptor protein-mediated multiprotein complexes. The recent generation of knockout mice for three members of the sodium-hydrogen regulatory factor (NHERF) family of PDZ adaptor proteins, namely NHERF1 (EBP50), NHERF2 (E3KARP) and NHERF3 (PDZK1), has helped to explain why NHERF1 is essential for both normal and mutant CFTR function. In addition, they have provided new insight into the molecular mechanisms of secretory diarrhoeas. Genetic ablation of members of the recently discovered Slc26 anion transporter gene family not only reproduced the phenotype of the genetic diseases that led to the discovery of the gene family, but also resulted in new insights into complex human diseases such as secretory diarrhoea, fructose-induced hypertension and urolithiasis.
    Experimental physiology 11/2008; 94(2):175 - 179. DOI:10.1113/expphysiol.2008.043018 · 2.67 Impact Factor
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    ABSTRACT: Diarrhea is widespread in intestinal diseases involving ischemia and/or hypoxia. Since hypoxia alters stimulated Cl(-) and water flux, we investigated the influence of such a physiologically and pathophysiologically important signal on expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Located on the apical membrane, this cAMP-activated Cl(-) channel determines salt and fluid transport across mucosal surfaces. Our studies revealed depression of CFTR mRNA, protein, and function in hypoxic epithelia. Chromatin immunoprecipitation identified a previously unappreciated binding site for the hypoxia inducible factor-1 (HIF-1), and promoter studies established its relevance by loss of repression following point mutation. Consequently, HIF-1 overexpressing cells exhibited significantly reduced transport capacity in colorimetric Cl(-) efflux studies, altered short circuit measurements, and changes in transepithelial fluid movement. Whole-body hypoxia in wild-type mice resulted in significantly reduced small intestinal fluid and HCO(3)(-) secretory responses to forskolin. Experiments performed in Cftr(-/-) and Nkcc1(-/-) mice underlined the role of altered CFTR expression for these functional changes, and work in conditional Hif1a mutant mice verified HIF-1-dependent CFTR regulation in vivo. In summary, our study clarifies CFTR regulation and introduces the concept of a HIF-1-orchestrated response designed to regulate ion and fluid movement across hypoxic intestinal epithelia.
    The FASEB Journal 10/2008; 23(1):204-13. DOI:10.1096/fj.08-110221 · 5.04 Impact Factor
  • The Physiology Society 2008 Main Meeting (Cambridge), 14- 16 July, 2008, Cambridge, UK; 01/2008

Publication Stats

100 Citations
51.06 Total Impact Points


  • 2008–2013
    • Hannover Medical School
      • Department of Gastroenterology, Hepatology and Endocrinology
      Hanover, Lower Saxony, Germany