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

Slattery, C., Jang, Y., Kruger, W. A., Hryciw, D. H., Lee, A. and Poronnik, P. (2013) gamma-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells. British Journal of Pharmacology, 169 6: 1239-1251. doi:10.1111/bph.12214


Author Slattery, C.
Jang, Y.
Kruger, W. A.
Hryciw, D. H.
Lee, A.
Poronnik, P.
Title gamma-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells
Formatted title
γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2013-07
Sub-type Article (original research)
DOI 10.1111/bph.12214
Open Access Status
Volume 169
Issue 6
Start page 1239
End page 1251
Total pages 13
Place of publication United Kingdom
Publisher John Wiley & Sons
Collection year 2014
Language eng
Formatted abstract
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 γ-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 γ-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 γ-secretase inhibitor, compound E.

Key Results Treatment with albumin resulted in a number of pro-fibrotic effects, including up-regulation of fibronectin, TGF-β1 and the EGF-R. Interestingly, similar effects were observed in response to treatment with the γ-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 γ-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 γ-secretase and the EGF-R. These results suggest that the proposed use of γ-secretase inhibitors as anti-fibrotic agents requires further investigation.
Keyword Albuminuria
gamma-Secretase
Epidermal growth factor receptor
Renal epithelial cell
Renal fibrosis
Growth-factor receptor
Amyloid precursor protein
Regulated intramembrane proteolysis
Diabetic-nephropathy
EGF receptor
Alzheimers-disease
Angiotensin-II
Kinase-C
In-vivo
γ-secretase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2014 Collection
School of Biomedical Sciences Publications
 
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