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Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-18T17:29:53Z No. of bitstreams: 1 fabianaaparecidamayrinkdeoliveira.pdf: 602450 bytes, checksum: 44abccc7edd994e7c93876d1aac063dd (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-22T15:11:02Z (GMT) No. of bitstreams: 1 fabianaaparecidamayrinkdeoliveira.pdf: 602450 bytes, checksum: 44abccc7edd994e7c93876d1aac063dd (MD5) / Made available in DSpace on 2016-07-22T15:11:02Z (GMT). No. of bitstreams: 1 fabianaaparecidamayrinkdeoliveira.pdf: 602450 bytes, checksum: 44abccc7edd994e7c93876d1aac063dd (MD5) Previous issue date: 2011-02-24 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Justificativa e Objetivo: Independente da etiologia, a doença renal crônica (DRC) envolve fibrose generalizada e progressiva do tecido, atrofia tubular e a perda da função renal. Atualmente, as terapias eficazes para esta condição são escassas. Neste estudo, foram investigados os efeitos da terapia laser de baixa intensidade (LLLT) sobre a fibrose intersticial, que ocorre após obstrução ureteral unilateral (OUU) em ratos, um modelo experimental de doença renal crônica. Materiais e Métodos: Foram utilizados 32 ratos Wistar, 8 em cada grupo, machos, com 250 a 300g de peso aproximadamente e 8 semanas de idade. O rim obstruído de metade dos ratos, submetidos à OUU receberam dose única intra-operatória do LLLT (AlGaAs laser, 780 nm, 22,5 J / cm ², 30 mW, 30 segundos em cada um dos nove pontos). Após 14 dias, a fibrose renal foi avaliada pela coloração por picrosírius e medição da área transversal sob luz polarizada. Análise imunohistoquímica quantificou células do tecido renal que expressam marcadores de fibroblastos (FSP-1) e miofibroblastos (α-SMA). RT-PCR foi realizado para determinar a expressão de mRNA de genes chaves relacionados com a fibrose: TGF-β1, Smad3 e colágeno I (Col I). Resultados: No grupo OUU e tratado pelo LLLT os animais apresentaram menos fibrose renal do que os animais obstruídos (OUU). α-SMA, TGF-β1 e Smad3 foram aumentados no interstício renal de ratos OUU. LLLT reduziu a expressão de todas essas moléculas. LLLT não parece ter um efeito significativo no Col I ou FSP-1, que também foram induzidos por OUU. Conclusão: Pela primeira vez, nós mostramos que LLLT tem um efeito protetor em relação à fibrose intersticial renal. Entende-se que, atenuando a inflamação, a laserterapia pode impedir a ativação tubular e transdiferenciação, que são os dois processos principais que formam a fibrose renal no modelo OUU. / Background and Objective: Regardless of the etiology, chronic kidney disease (CKD) involves progressive widespread tissue fibrosis, tubular atrophy and loss of kidney function. At present, effective therapies to this condition are lacking. We investigated the effects of low level laser therapy (LLLT) on the interstitial fibrosis that occurs after unilateral ureteral obstruction (UUO) in rats, an experimental model of CKD. Study Design/Materials and Methods: We used 32 Wistar rats, 8 in each group, males, 250 to 300g weight and 8 weeks old. The occluded kidney of half of the Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm², 30 mW, 30 seconds on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining and measurement of the cross-sectional area under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (α-SMA) markers. RT-PCR was performed to determine the mRNA expression of key fibrosis-related genes, namely TGF-β1, Smad3 and collagen I (Col I). Results: The UUO-LLLT animals had less severe renal fibrosis than OUU animals. α- SMA, TGF-β1 and Smad3 were increased in the renal interstitium of UUO rats. LLLT reduced the expression of all of these molecules. LLLT did not appear to have a significant effect on Col I or FSP-1, which were also induced by UUO. Conclusion: For the first time, we showed LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.

Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry. Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion. Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.