Renal fibrosis: not just PAI-1 in the sky

Abstract

A delicate balance exists between ECM synthesis and degradation such that interruption of the corresponding pathways results in increased plasminogen activator inhibitor-1 (PAI-1), pathological matrix accumulation, and glomerulosclerosis. 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.

Figure 1

PAI-1 modulates scarring in a complex manner, including effects on cell migration, matrix turnover, and macrophage infiltration. Whereas increased t-PA promotes dissolution of matrix and subsequently lessens glomerulosclerosis, this matrix breakdown facilitates cell migration and epithelial-mesenchymal transition (EMT) and thus contributes to increased interstitial fibrosis. The effects of PAI-1 that facilitate enhanced macrophage infiltration in vivo are complex and have not yet been established. Macrophages have beneficial effects early in interstitial fibrosis and promote fibrosis later. The increased number of glomerular macrophages is linked to glomerulosclerosis. u-PA and its receptor and vitronectin also interact with PAI-1 and contribute to its final effects on fibrosis.