Repulsive guidance molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway

被引:7
作者
Liu, Jiangfeng [1 ]
Wang, Weiling [1 ]
Liu, Ming [1 ]
Su, Limin [1 ]
Zhou, Hong [1 ]
Xia, Yin [2 ]
Ran, Jianhua [3 ,4 ]
Lin, Herbert Y. [5 ]
Yang, Baoxue [1 ]
机构
[1] Peking Univ, Sch Basic Med Sci, Dept Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
[2] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China
[3] Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China
[4] Chongqing Med Univ, Neurosci Ctr, Chongqing, Peoples R China
[5] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol,Renal Div, Boston, MA USA
基金
中国国家自然科学基金;
关键词
PKD; Tubule branching; Smad1/5/8; Renal cyst; Kidney disease; POLYCYSTIC KIDNEY-DISEASE; BRANCHING MORPHOGENESIS; IN-VITRO; E-CADHERIN; CELL; APOPTOSIS; DRAGON; GROWTH; TUBULOGENESIS; ACTIVATION;
D O I
10.1016/j.cellsig.2016.08.015
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenetic disease that still lacks effective therapy. Repulsive guidance molecule b (RGMb), a co-receptor for bone morphogenetic proteins (BMPs) and a ligand for neogenin, is expressed in renal tubular epithelial cells. Previous studies showed that RGMb plays negative roles in several types of tumors and prevents the immune system from over activation. The present study was designed to explore the effects of RGMb in ADPKD development. We found that expression of RGMb in kidney was less in PKD mice than wild-type mice. With stimulation of 8-bromo-cAMP, RGMb-null embryonic kidneys had greater cyst index, though their ureteric bud branched less than wild-type mice at E13.5. Postnatal RGMb-null kidneys showed interstitial hyperplasia and decreased tubular structures, especially in the boundary area of renal cortex and medulla. RGMb overexpression dramatically inhibited cyst development and promoted tubulogenesis in MDCK cells grown in 3D collagen gels. Biochemical analysis showed increased p-Smad1/5/8 and decreased p-ERK in RGMb-overexpressing MDCK cells, suggesting modulated BMP signaling. Specific inhibition of p-Smad1/5/8 by LDN193189 reversed the suppression of RGMb on MDCK cyst model. These results reveal RGMb as a novel regulator for ADPKD by promoting renal tubule branching and regulating BMP signaling pathway. Elevating RGMb and enhancing p-Smad1/5/8 are promising new strategies to treat ADPKD. (C) 2016 Elsevier Inc. All rights reserved.
引用
收藏
页码:1842 / 1851
页数:10
相关论文
共 59 条
[1]   Forskolin and derivatives as tools for studying the role of cAMP [J].
Alasbahi, R. H. ;
Melzig, M. F. .
PHARMAZIE, 2012, 67 (01) :5-13
[2]  
[Anonymous], J AM SOC NEPHROL
[3]  
[Anonymous], 2015, EUR POLYM J
[4]   Structure of the Repulsive Guidance Molecule (RGM)-Neogenin Signaling Hub [J].
Bell, Christian H. ;
Healey, Eleanor ;
van Erp, Susan ;
Bishop, Benjamin ;
Tang, Chenxiang ;
Gilbert, Robert J. C. ;
Aricescu, A. Radu ;
Pasterkamp, R. Jeroen ;
Siebold, Christian .
SCIENCE, 2013, 341 (6141) :77-80
[5]   IMPAIRED TUBULOGENESIS OF CYST-DERIVED CELLS FROM AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEYS [J].
CARONE, FA ;
NAKAMURA, S ;
BACALLAO, R ;
NELSON, WJ ;
KHOKHA, M ;
KANWAR, YS .
KIDNEY INTERNATIONAL, 1995, 47 (03) :861-868
[6]   Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis [J].
Chen, D ;
Roberts, R ;
Pohl, M ;
Nigam, S ;
Kreidberg, J ;
Wang, ZM ;
Heino, J ;
Ivaska, J ;
Coffa, S ;
Harris, RC ;
Pozzi, A ;
Zent, R .
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2004, 287 (04) :F602-F611
[7]   The RGM/DRAGON family of BMP co-receptors [J].
Corradini, Elena ;
Babitt, Jodie L. ;
Lin, Herbert Y. .
CYTOKINE & GROWTH FACTOR REVIEWS, 2009, 20 (5-6) :389-398
[8]   GDNF/Ret signaling and the development of the kidney [J].
Costantini, F ;
Shakya, R .
BIOESSAYS, 2006, 28 (02) :117-127
[9]   Patterning a Complex Organ: Branching Morphogenesis and Nephron Segmentation in Kidney Development [J].
Costantini, Frank ;
Kopan, Raphael .
DEVELOPMENTAL CELL, 2010, 18 (05) :698-712
[10]   Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors [J].
Cuny, Gregory D. ;
Yu, Paul B. ;
Laha, Joydev K. ;
Xing, Xuechao ;
Liu, Ji-Feng ;
Lai, Carol S. ;
Deng, Donna Y. ;
Sachidanandan, Chetana ;
Bloch, Kenneth D. ;
Peterson, Randall T. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (15) :4388-4392