γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells

C. Slattery; Y. Jang; W. A. Kruger; D. H. Hryciw; A. Lee; P. Poronnik

doi:10.1111/bph.12214

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γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells

Journal article

Open access

Peer reviewed

γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells

C. Slattery, Y. Jang, W. A. Kruger, D. H. Hryciw, A. Lee and P. Poronnik

British Journal of Pharmacology, Vol.169(6), pp.1239-1251

2013

DOI: https://doi.org/10.1111/bph.12214

PMID: 23594166

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Abstract

albuminuria

γ-Secretase

epidermal growth factor receptor

renal epithelial cell

renal fibrosis

Background and Purpose Albuminuria is an important biomarker of renal dysfunction and is a major mediator of renal damage and fibrosis during kidney disease. The mechanisms underlying albumin-induced renal fibrosis remain unclear. There has been significant interest in -secretase activity in tubular epithelial cells in recent times; however, its potential role in albumin-induced fibrosis has not been investigated. Experimental Approach The primary aim of this study was to examine the role of -secretase in albumin-induced fibrotic effects in proximal tubular cells. The effects of increasing albumin concentrations on fibrosis indicators and mediators in the human HK-2 cell line were examined in the presence and absence of a -secretase inhibitor, compound E. Key Results Treatment with albumin resulted in a number of pro-fibrotic effects, including up-regulation of fibronectin, TGF-1 and the EGF-R. Interestingly, similar effects were observed in response to treatment with the -secretase inhibitor, compound E. Co-treatment of cells with albumin and an EGF-R inhibitor, AG-1478, resulted in significant inhibition of the observed pro-fibrotic effects, suggesting a major role for the EGF-R in albumin-induced fibrotic events. Albumin-induced effects on the EGF-R appeared to be mediated through inhibition of -secretase activity and were dependent on ERK-MAPK signalling. Conclusions and Implications These results provide novel insights into the mechanisms of albumin-induced fibrotic effects in tubular epithelial cells, suggesting important roles for the -secretase and the EGF-R. These results suggest that the proposed use of -secretase inhibitors as anti-fibrotic agents requires further investigation.

Details

Title: γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells
Authors: C. Slattery - University College Dublin
Y. Jang - The University of Queensland
W. A. Kruger - RMIT University
D. H. Hryciw - The University of Melbourne
A. Lee - The University of Queensland
P. Poronnik (Corresponding Author) - RMIT University
Publication details: British Journal of Pharmacology, Vol.169(6), pp.1239-1251
Publisher: John Wiley & Sons Ltd.
Date published: 2013
DOI: 10.1111/bph.12214
ISSN: 1476-5381; 0007-1188
PMID: 23594166
Grant note: This work was supported by project grant funding from the National Health and Medical Research Council of Australia (P. P.). C. S. is a Government of Ireland Research Fellow funded by the Irish Research Council for Science, Engineering and Technology.
Organisation Unit: School of Health - Biomedicine
Language: English
Record Identifier: 991187230602621
Output Type: Journal article

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