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      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

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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 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 (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 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.

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          Diverse Roles of TGF-β/Smads in Renal Fibrosis and Inflammation

          TGF-β1 has been long considered as a key mediator in renal fibrosis and induces renal scarring largely by activating its downstream Smad signaling pathway. Interestingly, while mice overexpressing active TGF-β1 develop progressive renal injury, latent TGF-β1 plays a protective role in renal fibrosis and inflammation. Under disease conditions, Smad2 and Smad3 are highly activated, while Smad7 is degraded through the ubiquitin proteasome degradation mechanism. In addition to TGF-β1, many pathogenic mediators such as angiotensin II and advanced glycation end products can also activate the Smad pathway via both TGF-β-dependent and independent mechanisms. Smads interact with other signaling pathways, such as the MAPK and NF-κB pathways, to positively or negatively regulate renal inflammation and fibrosis. Studies from gene knockout mice demonstrate that TGF-β1 acts by stimulating its downstream Smads to diversely regulate kidney injury. In the context of renal fibrosis and inflammation, Smad3 is pathogenic, while Smad2 and Smad7 are protective. Smad4 exerts its diverse roles by transcriptionally enhancing Smad3-mediated renal fibrosis while inhibiting NF-κB-driven renal inflammation via a Smad7-dependent mechanism. Furthermore, we also demonstrated that TGF-β1 acts by stimulating Smad3 to positively or negatively regulate microRNAs to exert its fibrotic role in kidney disease. In conclusion, TGF-β/Smad signaling is a major pathway leading to kidney disease. Smad3 is a key mediator in renal fibrosis and inflammation, whereas Smad2 and Smad7 are renoprotective. Smad4 exerts its diverse role in promoting renal fibrosis while inhibiting inflammation. Thus, targeting the downstream TGF-β/Smad3 signaling pathway by gene transfer of either Smad7 or Smad3-dependent microRNAs may represent a specific and effective therapeutic strategy for kidney disease.
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            Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

            Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.
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              Adriamycin nephropathy: a model of focal segmental glomerulosclerosis.

              Adriamycin nephropathy (AN) is a rodent model of chronic kidney disease that has been studied extensively and has enabled a greater understanding of the processes underlying the progression of chronic proteinuric renal disease. AN is characterized by podocyte injury followed by glomerulosclerosis, tubulointerstitial inflammation and fibrosis. Genetic studies have demonstrated a number of loci that alter both risk and severity of renal injury induced by Adriamycin. Adriamycin-induced renal injury has been shown in numerous studies to be modulated by both non-immune and immune factors, and has facilitated further study of mechanisms of tubulointerstitial injury. This review will outline the pharmacological behaviour of Adriamycin, and describe in detail the model of AN, including its key structural characteristics, genetic susceptibility and pathogenesis. © 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 June 2015
                2015
                : 10
                : 6
                : e0127090
                Affiliations
                [1 ]Semmelweis University, Institute of Pathophysiology, Budapest, Hungary
                [2 ]National Institute of Health (NIH/NIAAA/DICBR), Laboratory of Physiological Studies, Section on Oxidative Stress and Tissue Injury, Bethesda, Maryland, United States of America
                [3 ]University of Szeged, Faculty of Medicine, Department of Biochemistry, Szeged, Hungary
                [4 ]1 st Semmelweis University, Department of Pathology and Experimental Cancer Research; MTA-SE Tumor Progression Research Group, Budapest, Hungary
                University Medical Center Utrecht, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TC T. Krenacs GS PP PH. Performed the experiments: CIS GK KE EL MG MS CR T. Kaucsar NK T. Krenacs GS. Analyzed the data: CIS KE GK MS TC CR T. Kaucsar TC T. Krenacs GS PP PH. Contributed reagents/materials/analysis tools: PP T. Krenacs PH. Wrote the paper: CIS KE GS PP PH.

                Article
                PONE-D-14-55246
                10.1371/journal.pone.0127090
                4473269
                26086199
                09bba9fe-c636-42f3-89b7-9f0a7b06cd68
                Copyright @ 2015

                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

                History
                : 9 December 2014
                : 10 April 2015
                Page count
                Figures: 6, Tables: 3, Pages: 17
                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.
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