A novel single amino acid deletion impairs fibronectin function and causes familial glomerulopathy with fibronectin deposits: case report of a family

Abstract Background Glomerulopathy with fibronectin deposits is an autosomal dominant disease associated with proteinuria, hematuria, hypertension and renal function decline. Forty percent of the cases are caused by mutations in FN1, the gene that encodes fibronectin. Case presentation This report describes two cases of Glomerulopathy with fibronectin deposits, involving a 47-year-old father and a 14-year-old son. The renal biopsies showed glomeruli with endocapillary hypercellularity and large amounts of mesangial and subendothelial eosinophilic deposits. Immunohistochemistry for fibronectin was markedly positive. Whole exome sequencing identified a novel FN1 mutation that leads to an amino-acid deletion in both patients (Ile1988del), a variant that required primary amino-acid sequence analysis for assessment of pathogenicity. Our primary sequence analyses revealed that Ile1988 is very highly conserved among relative sequences and is positioned in a C-terminal FN3 domain containing heparin- and fibulin-1-binding sites. This mutation was predicted as deleterious and molecular mechanics simulations support that it can change the tertiary structure and affect the complex folding and its molecular functionality. Conclusion The current report not only documents the occurrence of two GFND cases in an affected family and deeply characterizes its anatomopathological features but also identifies a novel pathogenic mutation in FN1, analyzes its structural and functional implications, and supports its pathogenicity.https://deepblue.lib.umich.edu/bitstream/2027.42/152212/1/12882_2019_Article_1507.pd

Th1/Th2 balance on renal ischemia-reperfusion injury

A lesão renal induzida pela I/R é a principal causa de IRA nos rins nativos e nos rins transplantados, e estudos enfatizam a participação de células inflamatórias na sua patogênese, através da caracterização de lesão endotelial, infiltração leucocitária e a geração de mediadores inflamatórios pelas células epiteliais tubulares. Evidências recentes mostram que as células T CD4+ exercem um papel fundamental como mediadoras da agressão renal na I/R, ressaltando-se o envolvimento do balanço Th1/Th2 como um possível mecanismo efetor. o presente estudo foi realizado com o objetivo de desenvolver um modelo experimental de I/R renal em camundongos deficientes em IL-12 (representando defeito da via de ativação Th1) e em camundongos deficientes em IL-4 (representando defeito da via de ativação Th2), tendo como controles camundongos normais (selvagens), analisando-se as alterações funcionais e morfológicas provocadas pela agressão renal isquêmica, além de investigar a expressão molecular de HO-1 (um gene de proteção tecidual), de MCP-1 (uma quimiocina pró-inflamatória) e de t-bet (um transcrito envolvido na diferenciação Th1), visando caracterizar a influência da polarização Th1ITh2 da resposta imune na lesão renal induzida pela IIR. Mostramos que os camundongos deficientes em IL-4 apresentaram uma disfunção renal, caracterizada pelos níveis séricos medianos de uréia, significantemente mais acentuada que os camundongos deficientes em IL-12, em 24 horas (357 mg/dL, 205-452 versus 85 mg/dL, 62-217) e em 48 horas (357 mg/dL, 122-551 versus 66 mg/dL, 51-142) após a IIR renal, bem como um grau de …(au).BV UNIFESP: Teses e dissertaçõe

Detecção de RNAm de gama-IFN, IL-2, IL-4, iNOS e perforina em aloenxertos renais humanos com rejeição aguda irreversível, utilizando a reação em cadeia da polimerase

BV UNIFESP: Teses e dissertaçõe

Critical involvement of Th1-related cytokines in renal injuries induced by ischemia and reperfusion

Renal ischemia and reperfusion injury (IRI) is considered an inflammatory syndrome. To move forward in its pathogenesis, we exploited the role of several cytokines on renal damages triggered by IRI. Specifically to evaluate the role of Th1 immune profile in this system, IL-12, IFN-gamma, and IFN-gamma/IL-12 deficient (KO) mice on C57BL/6 background and their controls were subjected to IRI. In each group, blood and kidney samples were harvested. Renal function was evaluated by serum creatinine and renal morphometric analyses. Gene expression of IL-6 and HO-1 were also investigated by Q-PCR. IFN-gamma KO animals presented the highest impairment in renal function compared to controls. Conversely, IL-12 KO animals were absolutely protected and, in a lesser extent, IFN-gamma/IL-12 KO double knockout was also protected from IRI. Gene expression analyses showed higher expression of HO-1, a cytoprotective gene, and IL-6, a pro-inflammatory cytokine, in IFN-gamma deficient animals subjected to IRI. Our results confirm that Th1 related cytokines such as IL-12 and IFN-gamma are critically involved in renal ischemia and reperfusion injury. (C) 2008 Elsevier B.V. All rights reserved

Critical involvement of Th1-related cytokines in renal injuries induced by ischemia and reperfusion

Renal ischemia and reperfusion injury (IRI) is considered an inflammatory syndrome. To move forward in its pathogenesis, we exploited the role of several cytokines on renal damages triggered by IRI. Specifically to evaluate the role of Th1 immune profile in this system, IL-12, IFN-gamma, and IFN-gamma/IL-12 deficient (KO) mice on C57BL/6 background and their controls were subjected to IRI. in each group, blood and kidney samples were harvested. Renal function was evaluated by serum creatinine and renal morphometric analyses. Gene expression of IL-6 and HO-1 were also investigated by Q-PCR. IFN-gamma KO animals presented the highest impairment in renal function compared to controls. Conversely, IL-12 KO animals were absolutely protected and, in a lesser extent, IFN-gamma/IL-12 KO double knockout was also protected from IRI. Gene expression analyses showed higher expression of HO-1, a cytoprotective gene, and IL-6, a pro-inflammatory cytokine, in IFN-gamma deficient animals subjected to IRI. Our results confirm that Th1 related cytokines such as IL-12 and IFN-gamma are critically involved in renal ischemia and reperfusion injury. (C) 2008 Elsevier B.V. All rights reserved.Univ São Paulo, Inst Biomed Sci, Dept Immunol, Div Immunol,Lab Transplantat Immunobiol, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, EPM, Dept Med, Clin & Expt Immunol Lab,Nephrol Div, São Paulo, BrazilHosp Israelita Albert Einstein, IEP, São Paulo, BrazilUniv Fed Triangulo Mineiro, Dept Pathol, Uberaba, MG, BrazilUniversidade Federal de São Paulo, EPM, Dept Med, Clin & Expt Immunol Lab,Nephrol Div, São Paulo, BrazilWeb of Scienc