Integrin-linked kinase signaling promotes cyst growth and fibrosis in polycystic kidney disease

Archana Raman, Gail A. Reif, Yuqiao Dai, Aditi Khanna, Xiaogang Li, Lindsay Astleford, Stephen C. Parnell, James P. Calvet, Darren P. Wallace

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2708-2719
Number of pages12
JournalJournal of the American Society of Nephrology
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Raman, A., Reif, G. A., Dai, Y., Khanna, A., Li, X., Astleford, L., Parnell, S. C., Calvet, J. P., & Wallace, D. P. (2017). Integrin-linked kinase signaling promotes cyst growth and fibrosis in polycystic kidney disease. Journal of the American Society of Nephrology, 28(9), 2708-2719. https://doi.org/10.1681/ASN.2016111235