Peroxisome Proliferator-Activated Receptor-<mml:math id="E1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math> (PPAR-<mml:math id="E2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>γ</mml:mi></mml:math>) Agonists Attenuate the Profibrotic Response Induced by TGF-<mml:math id="E3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math>1 in Renal Interstitial Fibroblasts

Wang, Weiming; Liu, Feng; Chen, Nan

doi:https://doi.org/10.1155/2007/62641

Mediators of Inflammation

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Research Article | Open Access

Volume 2007 | Article ID 062641 | https://doi.org/10.1155/2007/62641

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Agonists Attenuate the Profibrotic Response Induced by TGF-β1 in Renal Interstitial Fibroblasts

Weiming Wang,¹Feng Liu,¹and Nan Chen¹

Received14 Aug 2007

Accepted25 Oct 2007

Published17 Dec 2007

Abstract

Background. Studies have shown that peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists could ameliorate renal fibrotic lesions in both diabetic nephropathy and nondiabetic chronic kidney diseases. In order to elucidate the antifibrotic mechanism of PPAR-γ agonists, we investigated the effects of PPAR-γ activation on TGF-β1-induced renal interstitial fibroblasts. Methods. In rat renal interstitial fibroblasts (NRK/49F), the mRNA expression of TGF-β1-induced α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin (FN) and collagen type III (Col III) were observed by reverse transcriptase-polymerase chain reaction (RT-PCR). The protein expressions of FN and Smads were observed by Western blot. Results. In NRK/49F, TGF-β1 enhanced CTGF, FN and Col III mRNA expression in a dose- and time-dependent manner. α-SMA, CTGF, FN and Col III mRNA and FN protein expression in 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2)-troglitazone- and ciglitazone-pretreated groups, respectively, were significantly decreased compared with the TGF-β1-stimulated group. TGF-β1 (5 ng/mL) enhanced p-Smad2/3 protein expression in a time-dependent manner. Compared with the TGF-β1-stimulated group, p-Smad2/3 protein induced by TGF-β1 in PPAR-γ agonists-pretreated groups significantly decreased with no statistical difference amongst the three pretreated groups. Conclusion. PPAR-γ agonists could inhibit TGF-β1-induced renal fibroblast activation, CTGF expression and ECM synthesis through abrogating the TGF-β1/Smads signaling pathway.

References

M. Zeisberg, F. Strutz, and G. A. Müller, “Role of fibroblast activation in inducing interstitial fibrosis,” Journal of Nephrology, vol. 13, supplement 3, pp. S111–S120, 2000.
View at: Google Scholar
Y. Guan and M. D. Breyer, “Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease,” Kidney International, vol. 60, no. 1, pp. 14–30, 2001.
View at: Publisher Site | Google Scholar
Y. Guan, Y. Zhang, L. Davis, and M. D. Breyer, “Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans,” American Journal of Physiology, vol. 273, no. 6, pp. F1013–F1022, 1997.
View at: Google Scholar
T. Yang, D. E. Michele, J. Park et al., “Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney,” American Journal of Physiology, vol. 277, no. 6, pp. F966–F973, 1999.
View at: Google Scholar
T. Ishizuka, O. Ito, L. Tan et al., “Regulation of cytochrome P-450 4A activity by peroxisome proliferator-activated receptors in the rat kidney,” Hypertension Research, vol. 26, no. 11, pp. 929–936, 2003.
View at: Publisher Site | Google Scholar
S. Wakino, K. Hayashi, S. Tatematsu et al., “Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats,” Hypertension Research, vol. 28, no. 3, pp. 255–262, 2005.
View at: Publisher Site | Google Scholar
A. B. Walker, E. K. Naderali, P. D. Chattington, R. E. Buckingham, and G. Williams, “Differential vasoactive effects of the insulin sensitizers rosiglitazone (BRL 49653) and troglitazone on human small arteries in vitro,” Diabetes, vol. 47, no. 5, pp. 810–814, 1998.
View at: Publisher Site | Google Scholar
L.-J. Ma, C. Marcantoni, M. F. Linton, S. Fazio, and A. B. Fogo, “Peroxisome proliferator-activated receptor- $γ$ agonist troglitazone protects against nondiabetic glomerulosclerosis in rats,” Kidney International, vol. 59, no. 5, pp. 1899–1910, 2001.
View at: Publisher Site | Google Scholar
J. Weissgarten, S. Berman, S. Efrati, M. Rapoport, Z. Averbukh, and L. Feldman, “Apoptosis and proliferation of cultured mesangial cells isolated from kidneys of rosiglitazone-treated pregnant diabetic rats,” Nephrology Dialysis Transplantation, vol. 21, no. 5, pp. 1198–1204, 2006.
View at: Publisher Site | Google Scholar
U. Panchapakesan, S. Sumual, C. A. Pollock, and X. Chen, “PPAR- $γ$ agonists exert antifibrotic effects in renal tubular cells exposed to high glucose,” American Journal of Physiology, vol. 289, no. 5, pp. F1153–F1158, 2005.
View at: Publisher Site | Google Scholar
B. Guo, D. Koya, M. Isono, T. Sugimoto, A. Kashiwagi, and M. Haneda, “Peroxisome proliferator-activated receptor- $γ$ ligands inhibit TGF- $β$ 1-induced fibronectin expression in glomerular mesangial cells,” Diabetes, vol. 53, no. 1, pp. 200–208, 2004.
View at: Publisher Site | Google Scholar
A. Maeda, S. Horikoshi, T. Gohda, T. Tsuge, K. Maeda, and Y. Tomino, “Pioglitazone attenuates TGF- $β$ 1-induction of fibronectin synthesis and its splicing variant in human mesangial cells via activation of peroxisome proliferator-activated receptor (PPAR) $γ$ ,” Cell Biology International, vol. 29, no. 6, pp. 422–428, 2005.
View at: Publisher Site | Google Scholar
A. Gumieniczek, “Effect of the new thiazolidinedione-pioglitazone on the development of oxidative stress in liver and kidney of diabetic rabbits,” Life Sciences, vol. 74, no. 5, pp. 553–562, 2003.
View at: Publisher Site | Google Scholar
H. Kasuga, Y. Ito, S. Sakamoto et al., “Effects of anti-TGF- $ß$ type II receptor antibody on experimental glomerulonephritis,” Kidney International, vol. 60, no. 5, pp. 1745–1755, 2001.
View at: Publisher Site | Google Scholar
S.-L. Lin, R.-H. Chen, Y.-M. Chen et al., “Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor,” Journal of the American Society of Nephrology, vol. 16, no. 9, pp. 2702–2713, 2005.
View at: Publisher Site | Google Scholar
F. Zheng, A. Fornoni, S. J. Elliot et al., “Upregulation of type I collagen by TGF- $ß$ in mesangial cells is blocked by PPAR- $?$ activation,” American Journal of Physiology, vol. 282, no. 4, pp. 639–648, 2002.
View at: Google Scholar
D.-H. Cho, Y. J. Choi, S. A. Jo, and I. Jo, “Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) gamma-dependent and PPAR gamma-independent signaling pathways,” Journal of Biological Chemistry, vol. 279, no. 4, pp. 2499–2506, 2004.
View at: Publisher Site | Google Scholar
H. Sawano, M. Haneda, T. Sugimoto, K. Inoki, D. Koya, and R. Kikkawa, “15-deoxy- $Δ^{12, 14}$ -prostaglandin $J_{2}$ inhibits IL-1 $β$ -induced cyclooxygenase-2 expression in mesangial cells,” Kidney International, vol. 61, no. 6, pp. 1957–1967, 2002.
View at: Publisher Site | Google Scholar
S. Zafiriou, S. R. Stanners, T. S. Polhill, P. Poronnik, C. A. Pollock et al., “Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses,” Kidney International, vol. 65, no. 5, pp. 1647–1653, 2004.
View at: Publisher Site | Google Scholar
F. J. Villarreal and J. Asbun, “Peroxisome proliferator-activated receptors ligands, oxidative stress, and cardiac fibroblast extracellular matrix turnover,” Hypertension, vol. 44, no. 5, pp. 621–622, 2004.
View at: Publisher Site | Google Scholar
T. Asano, M. Wakisaka, M. Yoshinari et al., “Peroxisome proliferator-activated receptor $?$ 1 (PPAR $?$ 1) expresses in rat mesangial cells and PPAR $?$ agonists modulate its differentiation,” Biochimica et Biophysica Acta, vol. 1497, no. 1, pp. 148–154, 2000.
View at: Publisher Site | Google Scholar
Y. Ping, H. Xiaohui, L. Yongxue, and Z. Yali, “Activation of peroxisome proliferator-activated receptor $α$ in human endothelial cells increases plasminogen activator inhibitor type-1 expression,” Chinese Medical Journal, vol. 116, no. 1, pp. 29–33, 2003.
View at: Google Scholar
S. Zafiriou, S. R. Stanners, S. Saad, T. S. Polhill, P. Poronnik, and C. A. Pollock, “Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts,” Journal of the American Society of Nephrology, vol. 16, no. 3, pp. 638–645, 2005.
View at: Publisher Site | Google Scholar
U. Panzer, A. Schneider, Y. Guan et al., “Effects of different PPAR $?$ -agonists on MCP-1 expression and monocyte recruitment in experimental glomerulonephritis,” Kidney International, vol. 62, no. 2, pp. 455–464, 2002.
View at: Publisher Site | Google Scholar
Y. Shi and J. Massagué, “Mechanisms of TGF- $β$ signaling from cell membrane to the nucleus,” Cell, vol. 113, no. 6, pp. 685–700, 2003.
View at: Publisher Site | Google Scholar
A. Leask and D. J. Abraham, “TGF- $β$ signaling and the fibrotic response,” The FASEB Journal, vol. 18, no. 7, pp. 816–827, 2004.
View at: Publisher Site | Google Scholar
K. C. Flanders, “Smad3 as a mediator of the fibrotic response,” International Journal of Experimental Pathology, vol. 85, no. 2, pp. 47–64, 2004.
View at: Publisher Site | Google Scholar
W. Wang, V. Koka, and H. Y. Lan, “Transforming growth factor- $β$ and Smad signalling in kidney diseases,” Nephrology, vol. 10, no. 1, pp. 48–56, 2005.
View at: Publisher Site | Google Scholar
J. Yang, C. Dai, and Y. Liu, “Hepatocyte growth factor suppresses renal interstitial myofibroblast activation and intercepts Smad signal transduction,” The American Journal of Pathology, vol. 163, no. 2, pp. 621–632, 2003.
View at: Google Scholar

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Copyright © 2007 Weiming Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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