PMID- 30332313 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20200309 IS - 1522-1466 (Electronic) IS - 1931-857X (Print) IS - 1522-1466 (Linking) VI - 315 IP - 6 DP - 2018 Dec 1 TI - Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease. PG - F1695-F1707 LID - 10.1152/ajprenal.00246.2018 [doi] AB - In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds alpha(V)beta(3)-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. By contrast, periostin does not stimulate the proliferation of normal human kidney cells. This difference in the response to periostin is due to elevated expression of alpha(V)beta(3)-integrins by cystic cells. To determine whether periostin accelerates cyst growth and fibrosis, we generated mice with conditional overexpression of periostin in the collecting ducts (CDs). Ectopic CD expression of periostin was not sufficient to induce cyst formation or fibrosis in wild-type mice. However, periostin overexpression in pcy/pcy ( pcy) kidneys significantly increased mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis; and accelerated the decline in renal function. Moreover, CD-specific overexpression of periostin caused a decrease in the survival of pcy mice. These pathological changes were accompanied by increased renal expression of vimentin, alpha-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD. FAU - Raman, Archana AU - Raman A AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Molecular and Integrative Physiology, University of Kansas Medical Center , Kansas City, Kansas. FAU - Parnell, Stephen C AU - Parnell SC AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Biochemistry and Molecular Biology, University of Kansas Medical Center , Kansas City, Kansas. FAU - Zhang, Yan AU - Zhang Y AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Reif, Gail A AU - Reif GA AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Dai, Yuqiao AU - Dai Y AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Khanna, Aditi AU - Khanna A AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Daniel, Emily AU - Daniel E AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - White, Corey AU - White C AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Vivian, Jay L AU - Vivian JL AD - Department of Pathology and Laboratory Medicine, University of Kansas Medical Center , Kansas City, Kansas. FAU - Wallace, Darren P AU - Wallace DP AD - The Jared Grantham Kidney Institute, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Molecular and Integrative Physiology, University of Kansas Medical Center , Kansas City, Kansas. AD - Department of Internal Medicine, University of Kansas Medical Center , Kansas City, Kansas. LA - eng GR - P30 GM122731/GM/NIGMS NIH HHS/United States GR - P30 CA168524/CA/NCI NIH HHS/United States GR - P20 GM103418/GM/NIGMS NIH HHS/United States GR - P30 DK106912/DK/NIDDK NIH HHS/United States GR - P30 DK079328/DK/NIDDK NIH HHS/United States GR - R01 DK081579/DK/NIDDK NIH HHS/United States GR - U54 HD090216/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181017 PL - United States TA - Am J Physiol Renal Physiol JT - American journal of physiology. Renal physiology JID - 100901990 RN - 0 (Cell Adhesion Molecules) RN - 0 (POSTN protein, human) RN - 0 (Pkhd1 protein, mouse) RN - 0 (Postn protein, mouse) RN - 0 (Receptors, Cell Surface) SB - IM CIN - Am J Physiol Renal Physiol. 2019 Jan 1;316(1):F159-F161. PMID: 30484349 MH - Adult MH - Aged MH - Animals MH - Case-Control Studies MH - Cell Adhesion Molecules/genetics/*metabolism MH - Cell Movement MH - *Cell Proliferation MH - Cells, Cultured MH - Disease Models, Animal MH - Disease Progression MH - Epithelial Cells/*metabolism/pathology MH - Extracellular Matrix/metabolism/pathology MH - Female MH - Fibrosis MH - Gene Expression Regulation MH - Genetic Predisposition to Disease MH - Humans MH - Kidney Tubules, Collecting/*metabolism/pathology MH - Male MH - Mice, Transgenic MH - Middle Aged MH - Phenotype MH - Polycystic Kidney, Autosomal Dominant/genetics/*metabolism/pathology MH - Receptors, Cell Surface/genetics MH - Signal Transduction MH - Time Factors MH - Up-Regulation PMC - PMC6336984 OTO - NOTNLM OT - autosomal dominant polycystic kidney disease OT - extracellular matrix OT - integrin OT - matricellular protein OT - proliferation COIS- D. P. Wallace is a consultant for Vertex Pharmaceuticals. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. EDAT- 2018/10/18 06:00 MHDA- 2019/09/17 06:00 PMCR- 2019/12/01 CRDT- 2018/10/18 06:00 PHST- 2018/10/18 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/10/18 06:00 [entrez] PHST- 2019/12/01 00:00 [pmc-release] AID - F-00246-2018 [pii] AID - 10.1152/ajprenal.00246.2018 [doi] PST - ppublish SO - Am J Physiol Renal Physiol. 2018 Dec 1;315(6):F1695-F1707. doi: 10.1152/ajprenal.00246.2018. Epub 2018 Oct 17.