Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain

Joles, Jaap A. and Szalay, Csaba Imre and Erdélyi, Katalin and Kökény, Gábor and Lajtár, Enikő and Godó, Mária and Révész, Csaba and Kaucsár, Tamás and Kiss, Norbert and Sárközy, Márta and Csont, Tamás and Krenács, Tibor and Szénási, Gábor and Pacher, Pál and Hamar, Péter (2015) Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain. PLOS ONE, 10 (6). e0127090. ISSN 1932-6203

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Abstract

Chronic renal fibrosis is the final common pathway of end stage renal disease caused by glomerular or tubular pathologies. Genetic background has a strong influence on the pro- gression of chronic renal fibrosis. We recently found that Rowett black hooded rats were resistant to renal fibrosis. We aimed to investigate the role of sustained inflammation and oxidative/nitrative stress in renal fibrosis progression using this new model. Our previous data suggested the involvement of podocytes, thus we investigated renal fibrosis initiated by doxorubicin-induced (5 mg/kg) podocyte damage. Doxorubicin induced progressive glomerular sclerosis followed by increasing proteinuria and reduced bodyweight gain in fibrosis-sensitive, Charles Dawley rats during an 8-week long observation period. In comparison, the fibrosis-resistant, Rowett black hooded rats had longer survival, milder proteinuria and reduced tubular damage as assessed by neutrophil gelatinase-associated lipocalin (NGAL) excretion, reduced loss of the slit diaphragm protein, nephrin, less glomer- ulosclerosis, tubulointerstitial fibrosis and matrix deposition assessed by periodic acid – Schiff, Picro-Sirius-red staining and fibronectin immunostaining. Less fibrosis was associ- ated with reduced profibrotic transforming growth factor-beta, (TGF- β 1) connective tissue growth factor (CTGF), and collagen type I alpha 1 (COL-1a1) mRNA levels. Milder inflam- mation demonstrated by histology was confirmed by less monocyte chemotactic protein 1 (MCP-1) mRNA. As a consequence of less inflammation, less oxidative and nitrative stress was obvious by less neutrophil cytosolic factor 1 (p47 phox ) and NADPH oxidase-2 (p91 phox ) mRNA. Reduced oxidative enzyme expression was accompanied by less lipid peroxidation as demonstrated by 4-hydroxynonenal (HNE) and less protein nitrosylation demonstrated PLOS ONE | DOI:10.1371/journal.pone.0127090 June 18, 2015 1/17 OPENACCESS Citation: Szalay CI, Erdélyi K, Kökény G, Lajtár E, Godó M, Révész C, et al. (2015) Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis- Resistant Rat Strain. PLoS ONE 10(6): e0127090. doi:10.1371/journal.pone.0127090 Academic Editor: Jaap A. Joles, University Medical Center Utrecht, NETHERLANDS Received: December 9, 2014 Accepted: April 10, 2015 Published: June 18, 2015 Copyright: © 2015 Szalay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Support was provided to P. Hamar from the Hungarian Research Fund: OTKA-ANN(FWF) 110810 and OTKA-SNN 114619, and to P. Pacher from the Intramural Research Program of NIAAA/NIH. P Hamar acknowledges support from the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the Merit Prize of the Semmelweis University. by nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of fibrosis, inflammation and oxidative/nitrative stress were sup- pressed in doxorubicin nephropathy in fibrosis-resistant Rowett black hooded rats underly- ing the importance of these pathomechanisms in the progression of renal fibrosis initiated by glomerular podocyte damage.

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