title: 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.
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 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-β1) 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.
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Csaba Imre
authors.initials: CI
authors.lastname: Szalay
authors.affiliation: National Institute of Health (NIH/NIAAA/DICBR), Laboratory of Physiological Studies, Section on Oxidative Stress and Tissue Injury, Bethesda, Maryland, United States of America.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdélyi
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Kökény
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Enikő
authors.initials: E
authors.lastname: Lajtár
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Godó
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Révész
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kaucsár
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Kiss
authors.affiliation: University of Szeged, Faculty of Medicine, Department of Biochemistry, Szeged, Hungary.
authors.forename: Márta
authors.initials: M
authors.lastname: Sárközy
authors.affiliation: University of Szeged, Faculty of Medicine, Department of Biochemistry, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Csont
authors.affiliation: 1st Semmelweis University, Department of Pathology and Experimental Cancer Research; MTA-SE Tumor Progression Research Group, Budapest, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenács
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Szénási
authors.affiliation: National Institute of Health (NIH/NIAAA/DICBR), Laboratory of Physiological Studies, Section on Oxidative Stress and Tissue Injury, Bethesda, Maryland, United States of America.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Semmelweis University, Institute of Pathophysiology, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Hamar
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000235:genetics; D018450:Disease Progression; D060467:Disease Resistance; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000150:complications; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D013045:Species Specificity; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; C526316:CCN2 protein, rat; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D008565:Membrane Proteins; D026361:Reactive Nitrogen Species; D053773:Transforming Growth Factor beta1; C113267:nephrin; D055513:Connective Tissue Growth Factor; C002744:3-nitrotyrosine; D014443:Tyrosine; D004317:Doxorubicin; C027576:4-hydroxy-2-nonenal