PDGF Receptor Tyrosine Kinase Inhibitor Suppresses Mesangial Cell Proliferation Involving STAT3 Activation

Overview

Journal Clin Exp Immunol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 2006 Apr 26

PMID 16634810

Citations 11

Authors

T Hirai

T Masaki

M Kuratsune

N Yorioka

N Kohno

Affiliations

Soon will be listed here.

Abstract

Proliferation of mesangial cells is a hallmark of glomerular disease, and understanding the regulatory mechanisms is critically important. The purpose of this study was to examine the relationship between mesangial cell proliferation and phosphorylated signal transducer and activator of transcription (STAT) 3 and to determine whether the PDGF receptor tyrosine kinase inhibitor STI 571 inhibited mesangial cell proliferation via modulation of STAT3. In this study, we investigated for the first time, the glomerular expression of phosphorylated STAT3 in paraffin sections from animals with experimental mesangial proliferative glomeronephritis. Phosphorylated STAT3 colocalized with many proliferating mesangial cells. We also demonstrated that treatment with STI 571 reduced mesangial cell proliferation and phosphorylated STAT3 signalling both in vitro and in vivo. In vivo, STI 571 treatment reduced the number of glomerular mesangial cells positive for both phosphorylated STAT3 and proliferating cell nuclear antigen. In summary, phosphorylated STAT3 is strongly expressed during mesangial cell proliferation and STI 571 induced suppression of mesangial cell proliferation involves inhibition of phosphorylated STAT3 signalling.

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References

Kakizaki Y, Kraft N, Atkins R . Differential control of mesangial cell proliferation by interferon-gamma. Clin Exp Immunol. 1991; 85(1):157-63. PMC: 1535702. DOI: 10.1111/j.1365-2249.1991.tb05697.x. View

Clarke H, Kocher H, Khwaja A, Kloog Y, Cook H, Hendry B . Ras antagonist farnesylthiosalicylic acid (FTS) reduces glomerular cellular proliferation and macrophage number in rat thy-1 nephritis. J Am Soc Nephrol. 2003; 14(4):848-54. DOI: 10.1097/01.asn.0000057543.55318.8b. View

Bharti A, Donato N, Aggarwal B . Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol. 2003; 171(7):3863-71. DOI: 10.4049/jimmunol.171.7.3863. View

Masaki T, Foti R, Hill P, Ikezumi Y, Atkins R, Nikolic-Paterson D . Activation of the ERK pathway precedes tubular proliferation in the obstructed rat kidney. Kidney Int. 2003; 63(4):1256-64. DOI: 10.1046/j.1523-1755.2003.00874.x. View

Bromberg J, Horvath C, Besser D, Lathem W, Darnell Jr J . Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol. 1998; 18(5):2553-8. PMC: 110635. DOI: 10.1128/MCB.18.5.2553. View

Striker L, Doi T, Elliot S, Striker G . The contribution of glomerular mesangial cells to progressive glomerulosclerosis. Semin Nephrol. 1989; 9(4):318-28. View

Yamamoto T, Wilson C . Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat. Kidney Int. 1987; 32(4):514-25. DOI: 10.1038/ki.1987.240. View

Johnson R, Garcia R, Pritzl P, Alpers C . Platelets mediate glomerular cell proliferation in immune complex nephritis induced by anti-mesangial cell antibodies in the rat. Am J Pathol. 1990; 136(2):369-74. PMC: 1877401. View

Gilbert R, Kelly D, McKay T, Chadban S, Hill P, Cooper M . PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis. Kidney Int. 2001; 59(4):1324-32. DOI: 10.1046/j.1523-1755.2001.0590041324.x. View

10.

Yanagita M, Arai H, Nakano T, Ohashi K, Mizuno K, Fukatsu A . Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. J Biol Chem. 2001; 276(45):42364-9. DOI: 10.1074/jbc.M107488200. View

11.

Bokemeyer D, Panek D, Kramer H, Lindemann M, Kitahara M, Boor P . In vivo identification of the mitogen-activated protein kinase cascade as a central pathogenic pathway in experimental mesangioproliferative glomerulonephritis. J Am Soc Nephrol. 2002; 13(6):1473-80. DOI: 10.1097/01.asn.0000017576.50319.ac. View

12.

Border W, Yamamoto T, Noble N . Transforming growth factor beta in diabetic nephropathy. Diabetes Metab Rev. 1996; 12(4):309-39. DOI: 10.1002/(SICI)1099-0895(199612)12:4<309::AID-DMR171>3.0.CO;2-A. View

13.

Daniel C, Wiede J, Krutzsch H, Ribeiro S, Roberts D, Murphy-Ullrich J . Thrombospondin-1 is a major activator of TGF-beta in fibrotic renal disease in the rat in vivo. Kidney Int. 2004; 65(2):459-68. DOI: 10.1111/j.1523-1755.2004.00395.x. View

14.

Ostendorf T, Kunter U, Grone H, Bahlmann F, Kawachi H, Shimizu F . Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol. 2001; 12(5):909-918. DOI: 10.1681/ASN.V125909. View

15.

Johnson R, Iida H, Alpers C, Majesky M, Schwartz S, Pritzi P . Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation. J Clin Invest. 1991; 87(3):847-58. PMC: 329873. DOI: 10.1172/JCI115089. View

16.

Floege J, Eng E, Young B, Johnson R . Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int Suppl. 1993; 39:S47-54. View

17.

Fogo A, Ichikawa I . Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol. 1989; 9(4):329-42. View

18.

Fukada T, Hibi M, Yamanaka Y, Fujitani Y, Yamaguchi T, Nakajima K . Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity. 1996; 5(5):449-60. DOI: 10.1016/s1074-7613(00)80501-4. View

19.

Zhang L, Nakazawa K, Shigematsu H . Participation of endothelial cells and transformed mesangial cells in remodeling of glomerular capillary loops in Thy-1 nephritis. Pathol Int. 2001; 51(4):227-39. DOI: 10.1046/j.1440-1827.2001.01196.x. View

20.

Ikezumi Y, Hurst L, Masaki T, Atkins R, Nikolic-Paterson D . Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation. Kidney Int. 2002; 63(1):83-95. DOI: 10.1046/j.1523-1755.2003.00717.x. View