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Gamma-secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells.


Br J Pharmacol. 2013 Apr 17;


Authors: Slattery C, Jang Y, Kruger WA, Hryciw DH, Lee A, Poronnik P


Abstract

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 upregulation 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 mitogen activated protein kinase signalling. CONCLUSIONS AND IMPLICATIONS: These results provide novel insights into 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.

PMID: 23594166 [PubMed - as supplied by publisher]