The role of bradykinin in the antifibrotic actions of perindoprilat on human mesangial cells.
BACKGROUND
Angiotensin-converting enzyme inhibitors (ACE-I) protect against the development of glomerulosclerosis using mechanisms partly dissociated from their systemic antihypertensive action. The aim of the current study was to delineate the mechanism of action underlying the antifibrotic effects of the ACE-I perindoprilat in the context of macrophage-mediated scarring in human mesangial cells.


METHODS
Mesangial cells were treated with macrophage-conditioned medium (MPCM) in the presence or absence of the ACE-I perindoprilat.


RESULTS
Forty micromol/L perindoprilat reduced MPCM-induced mesangial cell fibronectin levels by 19.4 +/- 0.6% (P < 0.001). Immunoprecipitation of 35S-methionine biosynthetically labeled fibronectin and Northern analysis suggested that the decrease in fibronectin levels was not caused by reduced synthesis. MPCM stimulated the production of matrix metalloproteinases (MMP) 2, 3, and 9 in mesangial cells; however, these were not significantly altered by ACE-I treatment, and neither was production of their tissue inhibitor of metalloproteinases (TIMP-1). Addition of exogenous bradykinin to MPCM-treated mesangial cells resulted in a 22.5 +/- 1.4% (P < 0.02) reduction in secreted fibronectin levels, while semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Southern blotting demonstrated that bradykinin B2 receptor expression was up regulated by 71 +/- 30% in MPCM-stimulated mesangial cells in response to ACE-I treatment (P= 0.032). Moreover, the bradykinin B2 receptor antagonist HOE 140 attenuated the beneficial effects of perindoprilat. MPCM-stimulated mesangial cell protein expression levels of plasminogen activator system components tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were altered after treatment with ACE-I.


CONCLUSIONS
These results suggest that ACE-I-induced renoprotection, in the context of macrophage-stimulated mesangial cell scarring, is mediated, at least in part, via the actions of bradykinin.
Pawluczyk
Izabella Z A
IZ
John Walls Renal Unit, Leicester General Hospital; and University of Leicester, Leicester, UK. izap1@le.ac.uk
Patel
Samita R
SR
Harris
Kevin P G
KP
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D065094:Bradykinin B2 Receptor Antagonists; D002478:Cells, Cultured; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism; D005355:Fibrosis; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016234:Kallikrein-Kinin System / Q000502:physiology; D010960:Plasminogen Activators / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; D005353:Fibronectins; D007211:Indoles; D043782:Receptor, Bradykinin B2; C053500:perindoprilat; C065679:icatibant; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D001920:Bradykinin