A mutant non-inhibiting plasminogen activator inhibitor type 1 (PAI-1), termed PAI-1R, which reduces endogenous PAI-1 activity, has been shown to inhibit albuminuria and reduce glomerulosclerosis in experimental diabetes.
Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.
A new study demonstrates that therapy with a mutant PAI-1 increases matrix turnover and reduces glomerulosclerosis by competing with endogenous PAI-1, suggesting therapeutic utility in the treatment of fibrotic renal disease.
These observations strongly support our hypothesis that PAI-1R reduces glomerulosclerosis by competing with endogenous PAI-1, restoring plasmin generation, inhibiting inflammatory cell infiltration, decreasing local TGF-beta1 concentration, and reducing matrix accumulation.
The potential importance of the renin angiotensin system in glomerular sclerosis is underscored by the effectiveness of therapies that aim to inhibit its manifold actions, including induction of plasminogen activator inhibitor-1 (PAI-1).
Most recently, it has become clear that PAI-1 also plays a pivotal role in progressive renal disease, both glomerulosclerosis and tubulointerstitial fibrosis.
Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis.
Since the ACE gene deletion polymorphism is a known risk factor for progressive glomerulosclerosis in chronic renal diseases, we have investigated the relationship between the ACE genotypes and the development of renal scarring after APN.
Glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equivalent glomerulosclerosis: no further treatment, ARB, AT2 receptor antagonist, or combination.
We investigated the role of the renin-angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in PAN and cholesterol-mediated GS.
We investigated the role of the renin-angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in PAN and cholesterol-mediated GS.