title: Repulsive guidance molecule b inhibits renal cyst development through the bone morphogenetic protein signaling pathway.
abstract: 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.
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors: Jiangfeng
authors: J
authors: Liu
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors: Weiling
authors: W
authors: Wang
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors: Ming
authors: M
authors: Liu
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors: Limin
authors: L
authors: Su
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
authors: Hong
authors: H
authors: Zhou
authors: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors: Yin
authors: Y
authors: Xia
authors: Department of Anatomy and Neuroscience Center, Chongqing Medical University, Chongqing, China.
authors: Jianhua
authors: J
authors: Ran
authors: Program in Membrane Biology, Renal Division, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors: Herbert Y
authors: HY
authors: Lin
authors: State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. Electronic address: baoxue@bjmu.edu.cn.
authors: Baoxue
authors: B
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins; D052177:Kidney Diseases, Cystic / Q000378:metabolism* / Q000473:pathology*; D007684:Kidney Tubules / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D050396:TRPP Cation Channels / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D015816:Cell Adhesion Molecules, Neuronal; D048049:Extracellular Signal-Regulated MAP Kinases; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; D050396:TRPP Cation Channels; C554430:LDN 193189; C483497:Rgmb protein, mouse
keywords: Kidney disease; PKD; Renal cyst; Smad1/5/8; Tubule branching