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Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/- mice by diminishing senescence of cholangiocytes.
Zhou, Tianhao; Wu, Nan; Meng, Fanyin; Venter, Julie; Giang, Thao K; Francis, Heather; Kyritsi, Konstantina; Wu, Chaodong; Franchitto, Antonio; Alvaro, Domenico; Marzioni, Marco; Onori, Paolo; Mancinelli, Romina; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco.
Afiliação
  • Zhou T; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Wu N; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Meng F; Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
  • Venter J; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA.
  • Giang TK; Academic Research Integration, Baylor Scott & White Healthcare, Temple, TX, 76504, USA.
  • Francis H; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Kyritsi K; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Wu C; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Franchitto A; Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
  • Alvaro D; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA.
  • Marzioni M; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
  • Onori P; Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77840, USA.
  • Mancinelli R; Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy.
  • Gaudio E; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
  • Glaser S; Department of Medicine, Gastroenterology, Sapienza, Rome, Italy.
  • Alpini G; Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti - University Hospital, Ancona, Italy.
Lab Invest ; 98(11): 1449-1464, 2018 11.
Article em En | MEDLINE | ID: mdl-29977037
ABSTRACT
Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. The aim of this study was to determine the effects of genetic depletion of SR in Mdr2-/- mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. 12 wk SR-/-, Mdr2-/-, and SR-/-/Mdr2-/- mice with corresponding wild-type mice were used for the in vivo studies. Immunohistochemistry or immunofluorescence was performed in liver sections for (i) biliary expression of SR; (ii) hematoxylin and eosin; (iii) intrahepatic biliary mass by CK-19; (iv) fibrosis by Col1a1 and α-SMA; (v) senescence by SA-ß-gal and p16; and (vi) angiogenesis by VEGF-A and CD31. Secretin (Sct) and TGF-ß1 levels were measured in serum and cholangiocyte supernatant by ELISA. In total liver, isolated cholangiocytes or HSCs, we evaluated the expression of fibrosis markers (FN-1 and Col1a1); senescence markers (p16 and CCL2); microRNA 125b and angiogenesis markers (VEGF-A, VEGFR-2, CD31, and vWF) by immunoblots and/or qPCR. In vitro, we measured the paracrine effect of cholangiocyte supernatant on the expression of senescent and fibrosis markers in human hepatic stellate cells (HHSteCs). The increased level of ductular reaction, fibrosis, and angiogenesis in Mdr2-/- mice was reduced in SR-/-/Mdr2-/- mice. Enhanced senescence levels in cholangiocytes from Mdr2-/- mice were reversed to normal in SR-/-/Mdr2-/- mice. However, senescence was decreased in HSCs from Mdr2-/- mice but returned to normal values in SR-/-/Mdr2-/- mice. In vitro treatment of HHSteCs with supernatant from cholangiocyte lacking SR (containing lower biliary levels of Sct-dependent TGF-ß1) have decreased fibrotic reaction and increased cellular senescence. Sct-induced TGF-ß1 secretion was mediated by microRNA 125b. Our data suggest that differential modulation of angiogenesis-dependent senescence of cholangiocytes and HSCs may be important for the treatment of liver fibrosis in cholangiopathies.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores dos Hormônios Gastrointestinais / Secretina / Colangite Esclerosante / Senescência Celular / Receptores Acoplados a Proteínas G / Cirrose Hepática Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores dos Hormônios Gastrointestinais / Secretina / Colangite Esclerosante / Senescência Celular / Receptores Acoplados a Proteínas G / Cirrose Hepática Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article