Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor–related protein 1–mediated integrin signaling
Kebin Hu, … , Wendy M. Mars, Youhua Liu
Kebin Hu, … , Wendy M. Mars, Youhua Liu
Published November 21, 2007
Citation Information: J Clin Invest. 2007;117(12):3821-3832. https://doi.org/10.1172/JCI32301.
View: Text | PDF
Research Article Nephrology

Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor–related protein 1–mediated integrin signaling

Abstract

The activation of interstitial fibroblasts to become α-SMA–positive myofibroblasts is an essential step in the evolution of chronic kidney fibrosis, as myofibroblasts are responsible for the production and deposition of the ECM components that are a hallmark of the disease. Here we describe a signaling pathway that leads to this activation. Tissue-type plasminogen activator (tPA) promoted TGF-β1–mediated α-SMA and type I collagen expression in rat kidney interstitial fibroblasts. This fibrogenic effect was independent of its protease activity but required its membrane receptor, the LDL receptor–related protein 1 (LRP-1). In rat kidney fibroblasts, tPA induced rapid LRP-1 tyrosine phosphorylation and enhanced β1 integrin recruitment by facilitating the LRP-1/β1 integrin complex formation. Blockade or knockdown of β1 integrin abolished type I collagen and α-SMA expression. Furthermore, inhibition of the integrin-linked kinase (ILK), a downstream effector of β1 integrin, or disruption of β1 integrin/ILK engagement, abrogated the tPA action, whereas ectopic expression of ILK mimicked tPA in promoting myofibroblast activation. In murine renal interstitium after obstructive injury, tPA and α-SMA colocalized with LRP-1, and tPA deficiency reduced LRP-1/β1 integrin interaction and myofibroblast activation. These findings show that tPA induces LRP-1 tyrosine phosphorylation, which in turn facilitates the LRP-1–mediated recruitment of β1 integrin and downstream ILK signaling, thereby leading to myofibroblast activation. This study implicates tPA as a fibrogenic cytokine that promotes the progression of kidney fibrosis.

Authors

Kebin Hu, Chuanyue Wu, Wendy M. Mars, Youhua Liu

×

Figure 2

tPA promotes myofibroblast activation by a mechanism independent of its protease activity.

Options: View larger image (or click on image) Download as PowerPoint
tPA promotes myofibroblast activation by a mechanism independent of its ...
(A) Plasmin inhibitor aprotinin (50 U/ml) did not affect the synergistic effect of tPA with TGF-β1 (0.5 ng/ml) on α-SMA induction in NRK-49F cells. (B) Zymographic analysis demonstrates that aprotinin (50 U/ml) was able to block the proteolytic activity of plasmin. (C) Non-enzymatic mutant tPA retained the ability to synergistically promote α-SMA expression induced by TGF-β1. NRK-49F cells were incubated with mouse recombinant non-enzymatic tPA in the absence or presence of TGF-β1, as indicated.