Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease
| Autor: | Stephen C. Parnell, Darren P. Wallace, Jay L. Vivian, Archana Raman, Gail A. Reif, Yan Zhang, Corey White, Yuqiao Dai, Emily Daniel, Aditi Khanna |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Pathology medicine.medical_specialty Time Factors Physiology Autosomal dominant polycystic kidney disease Renal function Mice Transgenic Receptors Cell Surface Periostin Extracellular matrix 03 medical and health sciences Cell Movement Fibrosis medicine Polycystic kidney disease Animals Humans Genetic Predisposition to Disease Cyst Kidney Tubules Collecting Cells Cultured Aged Cell Proliferation business.industry Matricellular protein Epithelial Cells Middle Aged Polycystic Kidney Autosomal Dominant medicine.disease Extracellular Matrix Up-Regulation Disease Models Animal Phenotype 030104 developmental biology Gene Expression Regulation Case-Control Studies Disease Progression Female business Cell Adhesion Molecules Signal Transduction |
| Zdroj: | American Journal of Physiology-Renal Physiology. 315:F1695-F1707 |
| ISSN: | 1522-1466 1931-857X |
| Popis: | 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 αVβ3-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 αVβ3-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, α-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. |
| Databáze: | OpenAIRE |
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