Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Journal of the American Society of Nephrology : JASN
Archana RamanDarren P Wallace

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,...Continue Reading

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Citations

Oct 18, 2018·American Journal of Physiology. Renal Physiology·Archana RamanDarren P Wallace
Nov 30, 2018·American Journal of Physiology. Renal Physiology·Elieser H WatanabeLuiz F Onuchic
Jan 19, 2019·International Journal of Molecular Sciences·Jinzhao He, Baoxue Yang
Nov 10, 2020·American Journal of Physiology. Renal Physiology·Yan ZhangDarren P Wallace
Mar 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Jinzhao HeBaoxue Yang
Jul 16, 2021·Scientific Reports·Marciana V SousaLuiz F Onuchic

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