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

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.