Angiotensin II receptor blockade ameliorates mesangioproliferative glomerulonephritis in rats through suppression of CTGF and PAI-1, independently of the coagulation system.
BACKGROUND
Previously we observed that the coagulation system promotes matrix protein accumulation through transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) expression in rat mesangioproliferative glomerulonephritis (MsPGN). Angiotensin II receptor blockers (ARBs) are known to suppress matrix accumulation in experimental MsPGN. In the present study, we investigated whether ARB suppresses MsPGN through inhibition of these profibrotic cytokines, and in relation to coagulation and fibrinolytic systems.


METHODS
MsPGN was induced in Wistar rats by intravenous injection of anti-Thy-1.1 monoclonal antibody, OX-7. As an ARB, olmesartan was orally administered in rat feed from the day of OX-7 injection (day 0) to day 8, when rats were sacrificed and kidney specimens were collected. The degrees of cellular proliferation, matrix production, coagulation factors, and inhibitory factor of fibrinolysis were evaluated.


RESULTS
Although blood pressure did not change in the normal, disease control, or treatment groups, the amount of urinary protein was significantly decreased in the ARB-treated groups, compared with the disease control group (p < 0.05). alpha-Smooth muscle actin expression was suppressed significantly in the treatment groups (p < 0.001). Blue-staining areas of trichrome, the number of proliferating cell nuclear antigen (PCNA)- or ED-1-positive cells, fibronectin and plasminogen activator inhibitor type 1 in glomeruli significantly decreased in the treatment groups (p < 0.05, respectively); however, fibrin-related antigen and factor V depositions were not suppressed in the treatment groups.


CONCLUSIONS
These results suggest that the ARB drug would ameliorate MsPGN in vivo, at least partly through CTGF and plasminogen activator inhibitor type 1 suppression, and independently of the local coagulation system in glomeruli.
Liu
Ning
N
Clinical Pharmacology & Therapeutics, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka, Japan.
Shimizu
Shinya
S
Ito-Ihara
Toshiko
T
Takagi
Kuniaki
K
Kita
Toru
T
Ono
Takahiko
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001777:Blood Coagulation; D055513:Connective Tissue Growth Factor; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D007093:Imidazoles / Q000008:administration & dosage*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013777:Tetrazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; C526316:CCN2 protein, rat; D007093:Imidazoles; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D013777:Tetrazoles; D055513:Connective Tissue Growth Factor; C437965:olmesartan