Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease
| Autor: | Aditi Khanna, Lindsay Astleford, Darren P. Wallace, Gail A. Reif, Stephen C. Parnell, James P. Calvet, Archana Raman, Xiaogang Li, Yuqiao Dai |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Heterozygote medicine.medical_specialty 030232 urology & nephrology Autosomal dominant polycystic kidney disease Apoptosis Protein Serine-Threonine Kinases Periostin urologic and male genital diseases Mice 03 medical and health sciences 0302 clinical medicine Fibrosis Internal medicine medicine Polycystic kidney disease Animals Humans Integrin-linked kinase Gene Silencing Renal Insufficiency Kidney Tubules Collecting Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation biology TOR Serine-Threonine Kinases Homozygote Matricellular protein General Medicine Polycystic Kidney Autosomal Dominant medicine.disease Basic Research 030104 developmental biology Endocrinology Nephrology Disease Progression biology.protein Cell Adhesion Molecules Proto-Oncogene Proteins c-akt Dilatation Pathologic Signal Transduction |
| Zdroj: | Journal of the American Society of Nephrology. 28:2708-2719 |
| ISSN: | 1533-3450 1046-6673 |
| Popis: | Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin. Pharmacologic inhibition or shRNA knockdown of ILK prevented periostin-induced Akt/mammalian target of rapamycin (mTOR) signaling and ADPKD cell proliferation in vitro Homozygous deletion of ILK in renal collecting ducts (CD) of Ilkfl/fl ;Pkhd1-Cre mice caused tubule dilations, apoptosis, fibrosis, and organ failure by 10 weeks of age. By contrast, Ilkfl/+ ;Pkhd1-Cre mice had normal renal morphology and function and survived >1 year. Reduced expression of ILK in Pkd1fl/fl ;Pkhd1-Cre mice, a rapidly progressive model of ADPKD, decreased renal Akt/mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis, and significantly improved renal function and animal survival. Additionally, CD-specific knockdown of ILK strikingly reduced renal cystic disease and fibrosis and extended the life of pcy/pcy mice, a slowly progressive PKD model. We conclude that ILK is critical for maintaining the CD epithelium and renal function and is a key intermediate for periostin activation of signaling pathways involved in cyst growth and fibrosis in PKD. |
| Databáze: | OpenAIRE |
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