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- 저자 : Lamprecht, Georg (검색결과 4 건)
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Lee, Ki-Ho,Bunick, David,Lamprecht, Georg,Choi, Inho,Bahr, Janice M. Asian Australasian Association of Animal Productio 2008 Animal Bioscience Vol.21 No.4
Our earlier studies showed that estrogen was involved in the regulation of fluid reabsorption in adult mouse efferent ductules (ED), through estrogen receptor (ER) ${\alpha}$ and $ER{\beta}$ by modulating gene expression of epithelial genes involved in ion homeostasis. However, little is known about the importance of $ER{\alpha}$ in the ED during postnatal development. Based on previous findings, we hypothesized that there should be a difference in the expression of epithelial ion transporters and anion producers in the ED of postnatal wild type (WT) and estrogen receptor ${\alpha}$ knockout (${\alpha}ERKO$) mice. Using absolute, comparative and semi-quantitative RT-PCR along with immunohistochemistry, we looked at expression levels of several genes in the ED across postnatal development. The presence of estrogen in the testicular fluid was indirectly ascertained by immunohistochemical detection of the P450 aromatase in the testis. There was no immunohistochemically detectable difference in the expression of P450 aromatase in the testes and ER${\beta}$ in the ED of WT and ${\alpha}$ERKO mice. ER${\alpha}$ was only detected in the ED of WT mice. The absence of ER${\alpha}$ in the ED of postnatally developing mice resulted in differential expression of mRNAs and/or proteins for carbonic anhydrase II, $Na^+/H^+$ exchanger 3, down-regulated in adenoma, cystic fibrosis transmembrane regulator, and $Na^+/K^+$ ATPase ${\alpha}$. Our data indicate that the absence of ER${\alpha}$ resulted in altered expression of an epithelial ion producer and transporters during postnatal development of mice. We conclude that the presence of ER${\alpha}$is important for regulation of the ED function during the prepubertal developmental and postpubertal period.
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Xiao, Fang,Li, Junhua,Singh, Anurag Kumar,Riederer, Brigitte,Wang, Jiang,Sultan, Ayesha,Park, Henry,Lee, Min Goo,Lamprecht, Georg,Scholte, Bob J.,De Jonge, Hugo R.,Seidler, Ursula Blackwell Publishing Ltd 2012 The Journal of physiology Vol.590 No.21
<P><B>Key points</B></P><P><P>Cystic fibrosis (CF) is a lethal disease characterized by low rates of epithelial Cl<SUP>−</SUP> and HCO<SUB>3</SUB><SUP>−</SUP> secretion and obstruction of the airways and gastrointestinal and reproductive organs by sticky mucus. HCO<SUB>3</SUB><SUP>−</SUP> secretion has recently been demonstrated to be necessary for mucus hydration.</P><P>The most frequent CF mutation is F508del. This mutant protein is usually degraded in the proteasome. New therapeutic strategies have been developed which deliver F508del to the plasma membrane.</P><P>Utilizing transgenic F508del mutant and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice, apical membrane expression of F508del protein was found to be associated with enhanced stimulation of intestinal HCO<SUB>3</SUB><SUP>−</SUP> secretion.</P><P>The predominant molecular mechanism for enhanced F508del HCO<SUB>3</SUB><SUP>−</SUP> stimulation appeared to be the activation of a Cl<SUP>−</SUP> recycling pathway, with Cl<SUP>−</SUP> exit via membrane‐resident F508del protein and Cl<SUP>−</SUP> entry in exchange for HCO<SUB>3</SUB><SUP>−</SUP> by apical Cl<SUP>−</SUP>/HCO<SUB>3</SUB><SUP>−</SUP> exchange. In contrast, the predominant molecular mechanism for cAMP‐activated HCO<SUB>3</SUB><SUP>−</SUP> secretion in WT intestine appears to be HCO<SUB>3</SUB><SUP>−</SUP> exit via CFTR itself.</P></P><P><B>Abstract </B> This study investigated whether expression of the common cystic fibrosis transmembrane conductance regulator (CFTR) mutant F508del in the apical membrane of enterocytes confers increased bicarbonate secretory capacity on the intestinal epithelium of F508del mutant mice compared to that of CFTR knockout (KO) mice. CFTR KO mice, F508del mutant mice (F508del) and wild‐type (WT) littermates were bred on the FVB/N background. F508del isolated brush border membrane (BBM) contained approximately 5–10% fully glycosylated band C protein compared to WT BBM. Similarly, the forskolin (FSK)‐induced, CFTR‐dependent short‐circuit current (Δ<I>I</I><SUB>sc</SUB>) of F508del mucosa was approximately 5–10% of WT, whereas the HCO<SUB>3</SUB><SUP>−</SUP> secretory response (<IMG src='/wiley-blackwell_img/equation/TJP_5291_mu1.gif' alt ='inline image'/>) was almost half that of WT in both duodenum and mid‐colon studied <I>in vitro</I> and <I>in vivo.</I> While WT intestine retained full FSK‐induced <IMG src='/wiley-blackwell_img/equation/TJP_5291_mu2.gif' alt ='inline image'/> in the absence of luminal Cl<SUP>−</SUP>, the markedly higher <IMG src='/wiley-blackwell_img/equation/TJP_5291_mu3.gif' alt ='inline image'/> than Δ<I>I</I><SUB>sc</SUB> in F508del intestine was dependent on the presence of luminal Cl<SUP>−</SUP>, and was blocked by CFTR inhibitors. The Ste20‐related proline–alanine‐rich kinases (SPAK/OSR1), which are downstream of the with‐no‐lysine (K) protein kinases (WNK), were rapidly phosphorylated by FSK in WT and F508del, but significantly more slowly in CFTR KO intestine. In conclusion, the data demonstrate that low levels of F508del membrane expression in the intestine of F508del mice significantly increased FSK‐induced HCO<SUB>3</SUB><SUP>−</SUP> secretion mediated by Cl<SUP>−</SUP>/HCO<SUB>3</SUB><SUP>−</SUP> exchange. However, in WT mucosa FSK elicited strong SPAK/OSR1 phosphorylation and Cl<SUP>−</SUP>‐independent HCO<SUB>3</SUB><SUP>−</SUP> efflux. This suggests that therapeutic strategies which deliver F508del to the apical membrane have the potential to significantly enhance epithelial HCO<SUB>3</SUB><SUP>−</SUP> secretion.</P>
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( Henusha D. Jhundoo ),( Tobias Siefen ),( Alfred Liang ),( Christoph Schmidt ),( John Lokhnauth ),( Brice Moulari ),( Arnaud B. Duneau ),( Yann Pellequer ),( Crilles Casper Larsen ),( Alf Lamprecht ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.5
5-amino salicylic acid (5-ASA) is a standard therapy for the treatment of mild to moderate forms of inflammatory bowel diseases (IBD) whereas more severe forms involve the use of steroids and immunosuppressive drugs. Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan that has shown epithelium protective effects in experimental colitis recently. In this study, both 5-ASA (30 mg/kg) and HA (15 mg/kg or 30 mg/kg) were administered rectally and investigated for their potential complementary therapeutic effects in moderate or severe murine colitis models. Intrarectal treatment of moderate and severe colitis with 5-ASA alone or HA alone at a dose of 30 mg/kg led to a significant decrease in clinical activity and histology scores, myeloperoxidase activity (MPO), TNF-α, IL-6 and IL-1β in colitis mice compared to untreated animals. The combination of HA (30 mg/kg) and 5-ASA in severe colitis led to a significant improvement of colitis compared to 5-ASA alone. Combined rectal therapy with HA and 5-ASA could be a treatment alternative for severe cases of IBD as it was the only treatment tested that was not significantly different from the healthy control group. This study further underlines the benefit of searching for yet unexplored drug combinations that show therapeutic potential in IBD without the need of designing completely new drug entities.
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