Tissue-type Plasminogen Activator Promotes Murine Myofibroblast Activation Through LDL Receptor-related Protein 1-mediated Integrin Signaling

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Nov 27

PMID 18037995

Citations 73

Authors

Kebin Hu

Chuanyue Wu

Wendy M Mars

Youhua Liu

Affiliations

Soon will be listed here.

Abstract

The activation of interstitial fibroblasts to become alpha-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-beta1-mediated alpha-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 beta1 integrin recruitment by facilitating the LRP-1/beta1 integrin complex formation. Blockade or knockdown of beta1 integrin abolished type I collagen and alpha-SMA expression. Furthermore, inhibition of the integrin-linked kinase (ILK), a downstream effector of beta1 integrin, or disruption of beta1 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 alpha-SMA colocalized with LRP-1, and tPA deficiency reduced LRP-1/beta1 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 beta1 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.

Citing Articles

Matrix metalloproteinases in kidney homeostasis and diseases: an update.

Tan R, Liu Y Am J Physiol Renal Physiol. 2024; 327(6):F967-F984.

PMID: 39361724 PMC: 11687849. DOI: 10.1152/ajprenal.00179.2024.

Research progress on miR-124-3p in the field of kidney disease.

Chen G, Wang Y, Zhang L, Yang K, Wang X, Chen X BMC Nephrol. 2024; 25(1):252.

PMID: 39112935 PMC: 11308398. DOI: 10.1186/s12882-024-03688-7.

Myofibroblast-derived exosomes enhance macrophages to myofibroblasts transition and kidney fibrosis.

Yu W, Song J, Chen S, Nie J, Zhou C, Huang J Ren Fail. 2024; 46(1):2334406.

PMID: 38575341 PMC: 10997357. DOI: 10.1080/0886022X.2024.2334406.

Dysregulated bidirectional epithelial-mesenchymal crosstalk: a core determinant of lung fibrosis progression.

Yao L, Xu Z, Davies D, Jones M, Wang Y Chin Med J Pulm Crit Care Med. 2024; 2(1):27-33.

PMID: 38558961 PMC: 7615773. DOI: 10.1016/j.pccm.2024.02.001.

CD44s-activated tPA/LRP1-NFκB pathway drives lamellipodia outgrowth in luminal-type breast cancer cells.

Qiu Y, Wang H, Guo Q, Liu Y, He Y, Zhang G Front Cell Dev Biol. 2023; 11:1224827.

PMID: 37842093 PMC: 10569302. DOI: 10.3389/fcell.2023.1224827.

References

Schacke W, Beck K, Pfeilschifter J, Koch F, Hattenbach L . Modulation of tissue plasminogen activator and plasminogen activator inhibitor-1 by transforming growth factor-beta in human retinal glial cells. Invest Ophthalmol Vis Sci. 2002; 43(8):2799-805. View

Huang S, Ling T, Tseng W, Huang Y, Tang F, Leal S . Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J. 2003; 17(14):2068-81. DOI: 10.1096/fj.03-0256com. View

Younes M, Kim S, Yigitbasi O, Mandal M, Jasser S, Yazici Y . Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Mol Cancer Ther. 2005; 4(8):1146-56. DOI: 10.1158/1535-7163.MCT-05-0078. View

Badid C, Vincent M, Fouque D, Laville M, Desmouliere A . Myofibroblast: a prognostic marker and target cell in progressive renal disease. Ren Fail. 2001; 23(3-4):543-9. DOI: 10.1081/jdi-100104736. View

Boukhalfa G, Desmouliere A, Rondeau E, Gabbiani G, Sraer J . Relationship between alpha-smooth muscle actin expression and fibrotic changes in human kidney. Exp Nephrol. 1996; 4(4):241-7. View

Nassar T, Akkawi S, Shina A, Haj-Yehia A, Bdeir K, Tarshis M . In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone. Blood. 2003; 103(3):897-902. DOI: 10.1182/blood-2003-05-1685. View

Yang J, Liu Y . Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 2001; 159(4):1465-75. PMC: 1850509. DOI: 10.1016/S0002-9440(10)62533-3. View

Riccalton-Banks L, Bhandari R, Fry J, Shakesheff K . A simple method for the simultaneous isolation of stellate cells and hepatocytes from rat liver tissue. Mol Cell Biochem. 2003; 248(1-2):97-102. DOI: 10.1023/a:1024184826728. View

Kretzler M, Teixeira V, Unschuld P, Cohen C, Wanke R, Edenhofer I . Integrin-linked kinase as a candidate downstream effector in proteinuria. FASEB J. 2001; 15(10):1843-5. DOI: 10.1096/fj.00-0832fje. View

10.

Nagai N, Yamamoto S, Tsuboi T, Ihara H, Urano T, Takada Y . Tissue-type plasminogen activator is involved in the process of neuronal death induced by oxygen-glucose deprivation in culture. J Cereb Blood Flow Metab. 2001; 21(6):631-4. DOI: 10.1097/00004647-200106000-00001. View

11.

Mars W, Zarnegar R, Michalopoulos G . Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Pathol. 1993; 143(3):949-58. PMC: 1887222. View

12.

Cosgrove D, Rodgers K, Meehan D, Miller C, BOVARD K, GILROY A . Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol. 2000; 157(5):1649-59. PMC: 1885718. DOI: 10.1016/s0002-9440(10)64802-x. View

13.

Li Y, Spataro B, Yang J, Dai C, Liu Y . 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Kidney Int. 2005; 68(4):1500-10. DOI: 10.1111/j.1523-1755.2005.00562.x. View

14.

Yang M, Huang H, Li J, Li D, Wang H . Tyrosine phosphorylation of the LDL receptor-related protein (LRP) and activation of the ERK pathway are required for connective tissue growth factor to potentiate myofibroblast differentiation. FASEB J. 2004; 18(15):1920-1. DOI: 10.1096/fj.04-2357fje. View

15.

Willnow T, Armstrong S, Hammer R, Herz J . Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc Natl Acad Sci U S A. 1995; 92(10):4537-41. PMC: 41979. DOI: 10.1073/pnas.92.10.4537. View

16.

Yee J, Yan L, Dominguez J, Allan E, Martin T . Plasminogen-dependent activation of latent transforming growth factor beta (TGF beta) by growing cultures of osteoblast-like cells. J Cell Physiol. 1993; 157(3):528-34. DOI: 10.1002/jcp.1041570312. View

17.

Tan R, Zhang J, Tan X, Zhang X, Yang J, Liu Y . Downregulation of SnoN expression in obstructive nephropathy is mediated by an enhanced ubiquitin-dependent degradation. J Am Soc Nephrol. 2006; 17(10):2781-91. DOI: 10.1681/ASN.2005101055. View

18.

Wu C . PINCH, N(i)ck and the ILK: network wiring at cell-matrix adhesions. Trends Cell Biol. 2005; 15(9):460-6. DOI: 10.1016/j.tcb.2005.07.002. View

19.

Legate K, Montanez E, Kudlacek O, Fassler R . ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol. 2006; 7(1):20-31. DOI: 10.1038/nrm1789. View

20.

Salicioni A, Gaultier A, Brownlee C, Cheezum M, Gonias S . Low density lipoprotein receptor-related protein-1 promotes beta1 integrin maturation and transport to the cell surface. J Biol Chem. 2003; 279(11):10005-12. DOI: 10.1074/jbc.M306625200. View