Background/Purpose: Lupus nephritis is an autoimmune disorder which is characterized by extracellular matrix accumulation driven by immune complex deposition and in which thrombosis and sclerosis play a role in the development of nephropathy. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of pro-fibrinolytic plasminogen activators uPA and tPA and its expression has been shown to be increased in renal biopsies obtained from patients with lupus nephritis. Several studies utilizing transgenic mice (KO or over-expressing) in models of lupus nephritis have demonstrated a role for PAI-1 in the kidney pathology associated with these models.  The purpose of these studies was to evaluate the contribution of PAI-1 inhibition of PAs to pathological changes in the kidney in an accelerated model of mouse lupus nephritis.

Methods: An adenovirus encoding IFNa was injected into lupus-prone NZB/W mice resulting in an accelerated model of glomerulonephritis. A monoclonal antibody that selectively prevents the binding of PAI-1 to its target PAs was administered ip twice weekly beginning at the time of adv-IFNa administration. Effect of PAI-1 neutralization on development of proteinuria, gene and protein expression and histological changes in the kidney, and protein circulating in the plasma was assessed. Potential effects on immune cell expansion observed in this model were evaluated by FACS analysis. In vitro, the effect of blocking PAI-1 on extracellular matrix (ECM) degradation was evaluated in rat mesangial cells.

Results: PAI-1 was shown to be dramatically increased in the kidney (mRNA, IHC, ELISA) as well as in the plasma (ELISA) of diseased mice.  Inhibition of the PAI-1/PA interaction via treatment with the anti-PAI-1 antibody provided dose-dependent protection against the development of proteinuria and changes in sodium excretion. These effects were associated with normalization of fibrinolysis, ECM, cytokine and chemokine genes as well as histological changes in the glomerulus of the kidney.  Anti-PAI-1 treatment provided concentration-dependent degradation of ECM in rat mesangial cells providing further mechanistic support for the in vivo findings.

Conclusion: These data suggest that interfering with the PAI-1/PA interaction provides protection from the pathological changes in the kidney in this murine model downstream of immune complex deposition in the kidney.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blocking-the-serum-protease-inhibitor-activity-of-plasminogen-activator-inhibitor-1-protects-mice-from-development-of-glomerulonephritis-in-a-model-of-lupus-nephritis/