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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2009, Vol. 3 Issue (3) : 316-322    https://doi.org/10.1007/s11684-009-0045-2
Research articles
Effect of pirfenidone on renal tubulointerstitial fibrosis
Dixin LI MM , Hongbing ZENG MD , Chunyang JI MM ,
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
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Abstract Renal tubulointerstitial fibrosis (TIF) is the common end stage of various chronic renal diseases, and pirfenidone (PFD) is a novel, broad-spectrum anti-fibrotic compound but little is known about its effect and mechanism of action on renal TIF. In this work, we employed a unilateral ureteral obstruction (UUO) rat model to investigate the apoptosis of renal tubular epithelial cells (RTC) after PFD treatment. Thirty-five Sprague Dawley (SD) rats were randomized into three groups: sham-operated group (n=7), UUO group (n=14) and PFD group (n=14). All rats were sacrificed at day 7 or 14 after operation. Renal histology was studied by using periodic acid schiff reagent (PAS) and Masson trichromic stain (MASSON); apoptosis was detected by in situ terminal deoxynucleotide transferase-mediated dUTP-biotin nick end-labeling (TUNEL); tubular caspase-3 expression was assessed by immunohistochemistry. The content of malondialdehyde (MDA) and total activity of superoxide dismutase (T-SOD) in the renal cortex was determined by chemical colorimetry method. TIF, apoptosis of RTC, tubular expression of caspase-3 and the content of MDA were increased in the UUO group compared with those in the sham-operated group, and were ameliorated significantly by PFD treatment (P<0.05). The activity of SOD was decreased in the UUO group, but was improved by PFD treatment (P<0.05). Our results showed that PFD could ameliorate TIF in the UUO group, and the possible mechanism was by reducing the apoptosis of RTC, which involved oxidative stress and caspase-3.
Keywords pirfenidone      apoptosis      caspase 3      oxidative stress      
Issue Date: 05 September 2009
 Cite this article:   
Dixin LI MM,Chunyang JI MM,Hongbing ZENG MD. Effect of pirfenidone on renal tubulointerstitial fibrosis[J]. Front. Med., 2009, 3(3): 316-322.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-009-0045-2
https://academic.hep.com.cn/fmd/EN/Y2009/V3/I3/316
Nagata S. Apoptosis by death factor. Cell, 1997, 88(3): 355―365

doi: 10.1016/S0092-8674(00)81874-7
Truong L D, Choi Y J, Tsao C C, Ayala G, Sheikh-Hamad D, Nassar G, Suki W N. Renal cellapoptosis in chronic obstructive uropathy: the roles of caspases. Kidney Int, 2001, 60(3): 924―934

doi: 10.1046/j.1523-1755.2001.060003924.x
Gobe G C, Axelsen R A. Genesis of renal tubularatrophy in experimental hydronephrosis in the rat. Role of apoptosis. Lab Invest, 1987, 56(3): 273―281
Hagimoto N, Kuwano K, Kawasaki M, Yoshimi M, Kaneko Y, Kunitake R, Maeyama T, Tanaka T, Hara N. Induction of interleukin-8 secretion and apoptosis inbronchiolar epithelial cells by Fas ligation. Am J Respir Cell Mol Boil, 1999, 21(3): 436―445
Faouzi S, Burckhardt B E, Hanson J C, Campe C B, Schrum L W, Rippe R A, Maher J J. Anti-fas induces hepaticchemokines and promotes inflammation by an NFκB-independent,caspase-3-dependent pathway. J Biol Chem, 2001, 276(52): 49077―49082

doi: 10.1074/jbc.M109791200
Docherty N G, O'Sullivan O E, Healy D A, Fitzpatrick J M, Watson R W. Evidence that inhibitionof tubular cell apoptosis protects against renal damage and developmentof fibrosis following ureteric obstruction. Am J Physiol Renal Physiol, 2006, 290(1): 4―13

doi: 10.1152/ajprenal.00045.2005
Daemen M A, van’t Veer C, Denecker G, Heemskerk V H, WolfsClauss M TG, Vandenabeele P, Buurman W A. Inhibition of apoptosis induced by ischemia-reperfusionprevents inflammation. J Clin Invest, 1999, 104(5): 541―549

doi: 10.1172/JCI6974
Choi Y J, Baranowska-Daca E, Nguyen V, Koji T, Ballantyne C M, Sheikh-Hamad D, Suki W N, Truong L D. Mechanism of chronic obstructive uropathy:increased expression of apoptosis-promoting molecules. Kidney Int, 2000, 58(4): 1481―1491

doi: 10.1046/j.1523-1755.2000.00310.x
Raghu G, Johnson W C, Lockhart D, Mageto Y. Treatmentof idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open label Phase II study. Am J Respir Crit Care Med, 1999, 159(4 pt1): 1061―1069
Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T. Open-label compassionate use one year-treatment withpirfenidone to patients with chronic pulmonary fibrosis. Intern Med, 2002, 41(12): 1118―1123

doi: 10.2169/internalmedicine.41.1118
Iyer S N, Gurujeyalakshmi G, Giri S N. Effects of pirfenidone on procollagen gene expressionat the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther, 1999, 289(1): 211―218
Armendáriz-Borunda J, Islas-Carbajal MC, Meza-García E, Rincón A R, Lucano S, Sandoval A S, Salazar A, Berumen J, Alvarez A, Covarrubias A, Aréchiga G, García L. A pilot study in patientswith established advanced liver fibrosis using pirfenidone. Gut, 2006, 55(11): 1663―1665

doi: 10.1136/gut.2006.107136
García L, Hernández I, Sandoval A, Salazar A, Garcia J, Vera J, Grijalva G, Muriel P, Margolin S, Armendariz-Borunda J. Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol, 2002, 37(6): 797―805

doi: 10.1016/S0168-8278(02)00272-6
Mirkovic S, Seymour A M, Fenning A, Strachan A, Margolin S B, Taylor S M, Brown L. Attenuationof cardiac fibrosis by pirfenidone and amiloride in DOCA2 salt hypertensiverats. Br J Pharmacol, 2002, 135(4): 961―968

doi: 10.1038/sj.bjp.0704539
Miric G, Dallemagne C, Endre Z, Margolin S, Taylor S M, Brown L. Reversal of cardiac and renal fibrosis by pirfenidoneand spironolactone in streptozotocin diabetic rats. Br J Pharmacol, 2001, 133(5): 687―694

doi: 10.1038/sj.bjp.0704131
Cho M E, Smith D C, Branton M H, Penzak S R, Kopp J B. Pirfenidone slows renal function declinein patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol, 2007, 2(5): 906―913

doi: 10.2215/CJN.01050207
Shimizu T, Kuroda T, Hata S, Fukagawa M, Margolin S B, Kurokawa K. Pirfenidone improves renal function and fibrosis in thepostobstructed kidney. Kidney Int, 1998, 54(1): 99―109

doi: 10.1046/j.1523-1755.1998.00962.x
Hewitson T D, Kelynack K J, Tait M G, Martic M, Jones C L, Margolin S B, Becker G J. Pirfenidone reduces in vitrorat renal fibroblast activation and mitogenesis. J Nephrol, 2001, 14(6): 453―460
Shihab F S, Bennett W M, Yi H, Andoh T F. Effect ofPirfenidone on Apoptosis-Regulatory Genes in Chronic CyclosporineNephrotoxicity. Transplantation, 2005, 79(4): 419―426

doi: 10.1097/01.TP.0000151721.99418.48
Lieberthal W, Triaca V, Levine J. Mechanism s of death induced by cisplatin in proximaltubular epithelial cells: apoptosis vs necrosis. Am J Physiol, 1996, 270(4 Pt 2): F700―708
Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T, Brodsky S, Goligorsky M S. Oxidative and nitrosativestress in acute renal ischemia. Am J PhysiolRenal Physiol, 2001, 281(5): F948―957
Ricardo S D, Ding G, Eufemio M, Diamond J R. Antioxidant expression in experimental hydronephrosis: role of mechanicalstretch and growth factors. Am J PhysiolRenal Physiol, 1997, 272(6 Pt 2): 789―798
Sugiyama H, Kobayashi M, Wang D H, Sunami R, Maeshima Y, Yamasaki Y, Masuoka N, Kira S, Makino H. Telmisartaninhibits both oxidative stress and renal fibrosis after unilateralureteral obstruction in acatalasemic mice. Nephrol Dial Transplant, 2005, 20(12): 2670―2680

doi: 10.1093/ndt/gfi045
Klahr S, Morrissey J. Obstructive nephropathy andrenal fibrosis. Am J Physiol Renal Physiol, 2002, 283(5): F861―F875
Li M, Ona V O, Guégan C, Chen M, Jackson-Lewis V, Andrews L J, Olszewski A J, Stieg P E, Lee J P, Przedborski S, Friedlander R M. Functional role of caspase-1and caspase-3 in an ALS transgenic mouse model. Science, 2000, 288(5464): 335―339

doi: 10.1126/science.288.5464.335
Cuttle L, Zhang X J, Endre Z H, Winterford C, Gobe G C. Bcl-X(L) translocation inrenal tubular epithelial cells in vitro protects distal cells fromoxidative stress. Kidney Int, 2001, 59(5): 1779―1788

doi: 10.1046/j.1523-1755.2001.0590051779.x
Nowzari F B, Davidson S D, Eshghi M, Mallouh C, Tazaki H, Konno S. Adverse effects of oxidative stress on renal cells andits prevention by antioxidants. Mol Urol, 2000, 4(1): 15―19
Emanuele S, Calvaruso G, Lauricella M, Giuliano M, Bellavia G, D'Anneo A, Vento R, Tesoriere G. Apoptosis induced in hepatoblastomaHepG2 cells by the proteasome inhibitor MG132 is associated with hydrogenperoxide production, expression of Bcl-XS and activation of caspase-3. Int J Oncok, 2002, 21(4): 857―865
Tian B, Liu J, Bitterman P B, Bache R J. Mechanismsof cytokine induced NO-mediated cardiac fibroblast apoptosis. Am J Physiol Heart Circ Physiol, 2002, 283(5): H1958―1967
Woo S H, Park I C, Park M J, Lee H C, Lee S J, Chun Y J, Lee S H, Hong S I, Rhee C H. Arsenictrioxide induces apoptosis through a reactive oxygen species-dependentpathway and loss of mito-chondrial membrane potential in HeLa cells. Int J Oncol, 2002, 21(1): 57―63
Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel anti-fibrotic agentpirfenidone suppresses tumor necrosis factor2alpha at the translationallevel. Eur J Pharmacol, 2002, 446(123): 177―185

doi: 10.1016/S0014-2999(02)01758-2
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