Angiotensin II Receptor Blockade Ameliorates Mesangioproliferative Glomerulonephritis in Rats through Suppression of CTGF and PAI-1, Independently of the Coagulation System

Abstract

Background: Previously we observed that the coagulation system promotes matrix protein accumulation through transforming growth factor (TGF)-β 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). α-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.

Inhibitory Effects of Salvianolic Acid B on the High Glucose-Induced Mesangial Proliferation via NF-.KAPPA.B-Dependent Pathway

“…25,26) Regardless of different original mechanisms, mesangial cells proliferation might be believed to play predominant roles in the pathogenesis of progressive renal disease. [27][28][29] Hypertrophy of glomerular mesangial cells was associated with the appearance of proteinuria, glomerulosclerosis, and progressive renal failure in many animal models. 30) Therefore, the clinical suppression of mesangial overgrowth is critical to prevent renal failure.…”

Angiotensin II and Its Role in Tubular Epithelial to Mesenchymal Transition Associated with Chronic Kidney Disease

“…Blockade of the AT1 receptor attenuates increased CTGF expression in diabetes [Bolos et al, 2003], in the obstructed kidney of rats after UUO [Esteban et al, 2004], in mesangioproliferative glomerulonephritis [Liu et al, 2007], in aldosterone/salt-treated hypertensive rats [Fan et al, 2006] and in Ang-II-infused rats [Ruiz-Ortega et al, 2003]. By contrast, treatment with an AT2 receptor antagonist did not reduce CTGF expression or renal fibrosis [Ruiz-Ortega et al, 2003;Esteban et al, 2004].…”

The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases

“…95 Indirect inhibition of pAI-1 numerous agents that act indirectly but nevertheless can reduce plasma Pai-1 activity or levels effectively are available. aCe inhibitors, 96,97 angiotensin receptor blockers, 98,99 aldosterone antagonists, 40 insulin-sensitizing agents (including peroxisome proliferator-activated receptor…”