title: Perindoprilat modulates the activity of lipoprotein receptor-related protein in human mesangial cells.
abstract: Low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic receptor implicated in the modulation of a number of cellular processes, including the turnover of proteases and the degradation of extracellular matrix proteins. As such, it can play a key role in the control of fibrosis. The aim of this investigation was to ascertain whether the anti-fibrotic effects exerted by the angiotensin-converting enzyme inhibitor (ACE-I) perindoprilat on macrophage-conditioned medium (MPCM)-injured human mesangial cells can be modulated by this receptor. Addition of receptor-associated protein to MPCM-injured mesangial cells with and without ACE-I increased the amount of tissue plasminogen activator protein detected in mesangial cell culture supernatants without affecting the protein levels of plasminogen activator inhibitor-1. The ability of ACE-I to reduce fibronectin was diminished in the presence of receptor-associated protein. ACE-I induced an increase in mesangial cell MMP9 mRNA, but reduced the MMP9 enzyme activity detected in mesangial cell supernatants. Mesangial cell lysates from ACE-I-treated cells were able to bind immobilized fibronectin at higher dilutions than cell lysates from untreated cells. Flow cytometry showed that MPCM induced an increase in LRP surface expression in mesangial cells over that in control cells and that this expression was further increased by ACE-I treatment. The increase in LRP expression in response to ACE-I was also observed by Western blotting. Northern blot analysis of RNA extracted from cells following a 24-h exposure to MPCM with and without ACE-I demonstrated that there was no change in LRP mRNA expression upon ACE-I treatment. In conclusion, we show that ACE-I treatment is able to modulate mesangial cell-surface expression of LRP, providing an additional mechanism whereby ACE-Is can mediate anti-fibrotic actions independent of their hemodynamic actions.
authors.affiliation: John Walls Renal Unit, Leicester General Hospital, and Department of Infection, Immunity, and Inflammation, University of Leicester, UK. izap1@le.ac.uk
authors.forename: Izabella Z A
authors.initials: IZ
authors.lastname: Pawluczyk
authors.forename: Samita R
authors.initials: SR
authors.lastname: Patel
authors.forename: Kevin P G
authors.initials: KP
authors.lastname: Harris
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis*; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017077:Culture Media, Conditioned; D005353:Fibronectins; D007211:Indoles; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1; C053500:perindoprilat; D010959:Tissue Plasminogen Activator