PMID- 26086199 OWN - NLM STAT- MEDLINE DCOM- 20160425 LR - 20220316 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 6 DP - 2015 TI - 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. PG - e0127090 LID - 10.1371/journal.pone.0127090 [doi] LID - e0127090 AB - 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 progression 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 glomerulosclerosis, tubulointerstitial fibrosis and matrix deposition assessed by periodic acid-Schiff, Picro-Sirius-red staining and fibronectin immunostaining. Less fibrosis was associated with reduced profibrotic transforming growth factor-beta, (TGF-beta1) connective tissue growth factor (CTGF), and collagen type I alpha 1 (COL-1a1) mRNA levels. Milder inflammation 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 (p47phox) and NADPH oxidase-2 (p91phox) mRNA. Reduced oxidative enzyme expression was accompanied by less lipid peroxidation as demonstrated by 4-hydroxynonenal (HNE) and less protein nitrosylation demonstrated by nitrotyrosine (NT) immunohistochemistry and quantified by Western blot. Our results demonstrate that mediators of fibrosis, inflammation and oxidative/nitrative stress were suppressed in doxorubicin nephropathy in fibrosis-resistant Rowett black hooded rats underlying the importance of these pathomechanisms in the progression of renal fibrosis initiated by glomerular podocyte damage. FAU - Szalay, Csaba Imre AU - Szalay CI AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Erdelyi, Katalin AU - Erdelyi K AD - National Institute of Health (NIH/NIAAA/DICBR), Laboratory of Physiological Studies, Section on Oxidative Stress and Tissue Injury, Bethesda, Maryland, United States of America. FAU - Kokeny, Gabor AU - Kokeny G AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Lajtar, Eniko AU - Lajtar E AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Godo, Maria AU - Godo M AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Revesz, Csaba AU - Revesz C AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Kaucsar, Tamas AU - Kaucsar T AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Kiss, Norbert AU - Kiss N AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Sarkozy, Marta AU - Sarkozy M AD - University of Szeged, Faculty of Medicine, Department of Biochemistry, Szeged, Hungary. FAU - Csont, Tamas AU - Csont T AD - University of Szeged, Faculty of Medicine, Department of Biochemistry, Szeged, Hungary. FAU - Krenacs, Tibor AU - Krenacs T AD - 1st Semmelweis University, Department of Pathology and Experimental Cancer Research; MTA-SE Tumor Progression Research Group, Budapest, Hungary. FAU - Szenasi, Gabor AU - Szenasi G AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. FAU - Pacher, Pal AU - Pacher P AD - National Institute of Health (NIH/NIAAA/DICBR), Laboratory of Physiological Studies, Section on Oxidative Stress and Tissue Injury, Bethesda, Maryland, United States of America. FAU - Hamar, Peter AU - Hamar P AD - Semmelweis University, Institute of Pathophysiology, Budapest, Hungary. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150618 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Aldehydes) RN - 0 (CCN2 protein, rat) RN - 0 (Ccl2 protein, rat) RN - 0 (Chemokine CCL2) RN - 0 (Membrane Proteins) RN - 0 (Reactive Nitrogen Species) RN - 0 (Transforming Growth Factor beta1) RN - 0 (nephrin) RN - 139568-91-5 (Connective Tissue Growth Factor) RN - 3604-79-3 (3-nitrotyrosine) RN - 42HK56048U (Tyrosine) RN - 80168379AG (Doxorubicin) RN - K1CVM13F96 (4-hydroxy-2-nonenal) SB - IM MH - Aldehydes/metabolism MH - Animals MH - Body Weight/drug effects MH - Chemokine CCL2/genetics MH - Connective Tissue Growth Factor/genetics MH - *Disease Progression MH - *Disease Resistance MH - Dose-Response Relationship, Drug MH - Doxorubicin/*toxicity MH - Fibrosis MH - Kidney/drug effects/*metabolism/*pathology MH - Male MH - Membrane Proteins/genetics MH - Oxidative Stress/*drug effects MH - Proteinuria/complications MH - Rats MH - Reactive Nitrogen Species/*metabolism MH - Species Specificity MH - Transforming Growth Factor beta1/genetics MH - Tyrosine/analogs & derivatives/metabolism PMC - PMC4473269 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/06/19 06:00 MHDA- 2016/04/26 06:00 PMCR- 2015/06/18 CRDT- 2015/06/19 06:00 PHST- 2014/12/09 00:00 [received] PHST- 2015/04/10 00:00 [accepted] PHST- 2015/06/19 06:00 [entrez] PHST- 2015/06/19 06:00 [pubmed] PHST- 2016/04/26 06:00 [medline] PHST- 2015/06/18 00:00 [pmc-release] AID - PONE-D-14-55246 [pii] AID - 10.1371/journal.pone.0127090 [doi] PST - epublish SO - PLoS One. 2015 Jun 18;10(6):e0127090. doi: 10.1371/journal.pone.0127090. eCollection 2015.