Macrophage Matrix Metalloproteinase-9 Mediates Epithelial-mesenchymal Transition in Vitro in Murine Renal Tubular Cells

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Jan 16

PMID 20075196

Citations 74

Authors

Thian Kui Tan

Guoping Zheng

Tzu-Ting Hsu

Ying Wang

Vincent W S Lee

Xinrui Tian

Yiping Wang

Qi Cao

Ya Wang

David C H Harris

Affiliations

Soon will be listed here.

Abstract

As a rich source of pro-fibrogenic growth factors and matrix metalloproteinases (MMPs), macrophages are well-placed to play an important role in renal fibrosis. However, the exact underlying mechanisms and the extent of macrophage involvement are unclear. Tubular cell epithelial-mesenchymal transition (EMT) is an important contributor to renal fibrosis and MMPs to induction of tubular cell EMT. The aim of this study was to investigate the contribution of macrophages and MMPs to induction of tubular cell EMT. The murine C1.1 tubular epithelial cell line and primary tubular epithelial cells were cultured in activated macrophage-conditioned medium (AMCM) derived from lipopolysaccharide-activated J774 macrophages. MMP-9, but not MMP-2 activity was detected in AMCM. AMCM-induced tubular cell EMT in C1.1 cells was inhibited by broad-spectrum MMP inhibitor (GM6001), MMP-2/9 inhibitor, and in AMCM after MMP-9 removal by monoclonal Ab against MMP-9. AMCM-induced EMT in primary tubular epithelial cells was inhibited by MMP-2/9 inhibitor. MMP-9 induced tubular cell EMT in both C1.1 cells and primary tubular epithelial cells. Furthermore, MMP-9 induced tubular cell EMT in C1.1 cells to an extent similar to transforming growth factor-beta. Transforming growth factor-beta-induced tubular cell EMT in C1.1 cells was inhibited by MMP-2/9 inhibitor. Our in vitro study provides evidence that MMPs, specifically MMP-9, secreted by effector macrophages can induce tubular cell EMT and thereby contribute to renal fibrosis.

Citing Articles

Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation.

Krauss T, Gurcinar I, Bourquain U, Hieber M, Krohmer E, Wu N Neoplasia. 2025; 60:101126.

PMID: 39842382 PMC: 11763858. DOI: 10.1016/j.neo.2025.101126.

Gut-liver translocation of pathogen Klebsiella pneumoniae promotes hepatocellular carcinoma in mice.

Wang X, Fang Y, Liang W, Cai Y, Wong C, Wang J Nat Microbiol. 2025; 10(1):169-184.

PMID: 39747695 PMC: 11726454. DOI: 10.1038/s41564-024-01890-9.

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.

A New Rat Model of Sacral Cord Injury Producing a Neurogenic Bladder and Its Functional and Mechanistic Studies.

Bai K, Hou Y, Zhang Z, Yuan F, Huang X, Liu P Biomolecules. 2024; 14(9).

PMID: 39334907 PMC: 11429646. DOI: 10.3390/biom14091141.

Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics.

Islamuddin M, Qin X Cell Death Discov. 2024; 10(1):229.

PMID: 38740765 PMC: 11091222. DOI: 10.1038/s41420-024-01996-3.

References

Kleiner S, Faisal A, Nagamine Y . Induction of uPA gene expression by the blockage of E-cadherin via Src- and Shc-dependent Erk signaling. FEBS J. 2007; 274(1):227-40. DOI: 10.1111/j.1742-4658.2006.05578.x. View

Zeisberg E, Potenta S, Sugimoto H, Zeisberg M, Kalluri R . Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol. 2008; 19(12):2282-7. PMC: 2588112. DOI: 10.1681/ASN.2008050513. View

Qi J, Chen N, Wang J, Siu C . Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol Biol Cell. 2005; 16(9):4386-97. PMC: 1196346. DOI: 10.1091/mbc.e05-03-0186. View

Orlichenko L, Radisky D . Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis. 2008; 25(6):593-600. DOI: 10.1007/s10585-008-9143-9. 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

Henderson N, MacKinnon A, Farnworth S, Kipari T, Haslett C, Iredale J . Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol. 2008; 172(2):288-98. PMC: 2312353. DOI: 10.2353/ajpath.2008.070726. View

Cheng S, Lovett D . Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003; 162(6):1937-49. PMC: 1868144. DOI: 10.1016/S0002-9440(10)64327-1. View

Fan J, Huang X, Ng Y, Nikolic-Paterson D, Mu W, Atkins R . Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. Am J Kidney Dis. 2001; 37(4):820-31. DOI: 10.1016/s0272-6386(01)80132-3. View

Yang J, Shultz R, Mars W, Wegner R, Li Y, Dai C . Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest. 2002; 110(10):1525-38. PMC: 151817. DOI: 10.1172/JCI16219. View

10.

Symowicz J, Adley B, Gleason K, Johnson J, Ghosh S, Fishman D . Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res. 2007; 67(5):2030-9. DOI: 10.1158/0008-5472.CAN-06-2808. View

11.

Mei J, Borchert G, Donald S, Phang J . Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of beta-catenin from membrane bound E-cadherin and formation of nuclear beta-catenin/LEF-1 complex. Carcinogenesis. 2003; 23(12):2119-22. DOI: 10.1093/carcin/23.12.2119. View

12.

Birkedal-Hansen H . Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995; 7(5):728-35. DOI: 10.1016/0955-0674(95)80116-2. View

13.

Rodriguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson R . Role of immunocompetent cells in nonimmune renal diseases. Kidney Int. 2001; 59(5):1626-40. DOI: 10.1046/j.1523-1755.2001.0590051626.x. View

14.

Hooke D, Gee D, Atkins R . Leukocyte analysis using monoclonal antibodies in human glomerulonephritis. Kidney Int. 1987; 31(4):964-72. DOI: 10.1038/ki.1987.93. View

15.

Lan H . Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens. 2002; 12(1):25-9. DOI: 10.1097/00041552-200301000-00005. View

16.

Jones C, Buch S, Post M, McCulloch L, Liu E, Eddy A . Pathogenesis of interstitial fibrosis in chronic purine aminonucleoside nephrosis. Kidney Int. 1991; 40(6):1020-31. DOI: 10.1038/ki.1991.310. View

17.

Moriyama T, Kawada N, Ando A, Yamauchi A, Horio M, Nagata K . Up-regulation of HSP47 in the mouse kidneys with unilateral ureteral obstruction. Kidney Int. 1998; 54(1):110-9. DOI: 10.1046/j.1523-1755.1998.00964.x. View

18.

Lenz O, Elliot S, Stetler-Stevenson W . Matrix metalloproteinases in renal development and disease. J Am Soc Nephrol. 2000; 11(3):574-581. DOI: 10.1681/ASN.V113574. View

19.

van Goor H, Ding G, Grond J, Schreiner G, Diamond J . Macrophages and renal disease. Lab Invest. 1994; 71(4):456-64. View

20.

Duffield J, Tipping P, Kipari T, Cailhier J, Clay S, Lang R . Conditional ablation of macrophages halts progression of crescentic glomerulonephritis. Am J Pathol. 2005; 167(5):1207-19. PMC: 1603796. DOI: 10.1016/S0002-9440(10)61209-6. View