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Sci Rep. 2018 Mar 21;8(1):4985. doi: 10.1038/s41598-018-23341-2.

Inhibition of Hedgehog signaling suppresses proliferation and microcyst formation of human Autosomal Dominant Polycystic Kidney Disease cells.

Author information

1
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
2
Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA.
3
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
4
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
5
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
6
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA. ptran@kumc.edu.
7
Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA. ptran@kumc.edu.

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutation of PKD1 or PKD2, which encode polycystin 1 and 2, respectively. The polycystins localize to primary cilia and the functional loss of the polycystin complex leads to the formation and progressive growth of fluid-filled cysts in the kidney. The pathogenesis of ADPKD is complex and molecular mechanisms connecting ciliary dysfunction to renal cystogenesis are unclear. Primary cilia mediate Hedgehog signaling, which modulates cell proliferation and differentiation in a tissue-dependent manner. Previously, we showed that Hedgehog signaling was increased in cystic kidneys of several PKD mouse models and that Hedgehog inhibition prevented cyst formation in embryonic PKD mouse kidneys treated with cAMP. Here, we show that in human ADPKD tissue, Hedgehog target and activator, Glioma 1, was elevated and localized to cyst-lining epithelial cells and to interstitial cells, suggesting increased autocrine and paracrine Hedgehog signaling in ADPKD, respectively. Further, Hedgehog inhibitors reduced basal and cAMP-induced proliferation of ADPKD cells and cyst formation in vitro. These data suggest that Hedgehog signaling is increased in human ADPKD and that suppression of Hedgehog signaling can counter cellular processes that promote cyst growth in vitro.

PMID:
29563577
PMCID:
PMC5862907
DOI:
10.1038/s41598-018-23341-2
[Indexed for MEDLINE]
Free PMC Article

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