Journal
CELLULAR SIGNALLING
Volume 28, Issue 12, Pages 1842-1851Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2016.08.015
Keywords
PKD; Tubule branching; Smad1/5/8; Renal cyst; Kidney disease
Categories
Funding
- National Natural Science Foundation of China grants (NSFC) [31200869, 81330074, 81170632, N_CUHK432/12, 81261160507]
- Hong Kong Research Grant Council (RGC)
- Research Fund for the Doctoral Program of Higher Education [20100001110047]
- 111 Project
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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.
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