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

• Published in: British journal of pharmacology Vol. 169; no. 6; pp. 1239 - 1251
• Main Authors: Slattery, C, Jang, Y, Kruger, W A, Hryciw, D H, Lee, A, Poronnik, P
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2013
• Subjects: albuminuria; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Benzodiazepinones - pharmacology; Cattle; Cell Line; Culture Media, Serum-Free; Endocytosis - drug effects; Enzyme Inhibitors - pharmacology; epidermal growth factor receptor; Fibronectins - secretion; Fibrosis; Humans; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Kidney Tubules, Proximal - secretion; MAP Kinase Signaling System - drug effects; Opossums; Proteolysis - drug effects; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; renal epithelial cell; renal fibrosis; Research Papers; Serum Albumin, Bovine - metabolism; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - secretion; Tyrphostins - pharmacology; Urothelium - drug effects; Urothelium - metabolism; Urothelium - pathology; Urothelium - secretion; γ‐secretase
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12214

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.