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1.
Am J Physiol Renal Physiol ; 319(4): F571-F578, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830537

RESUMO

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.


Assuntos
Proliferação de Células , Glomerulonefrite/enzimologia , Células Mesangiais/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Via de Sinalização Wnt , Amidas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fumaratos/farmacologia , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Fosforilação , Ratos Endogâmicos WKY , ATPases Vacuolares Próton-Translocadoras , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt4/metabolismo , beta Catenina/metabolismo
2.
Nephrology (Carlton) ; 21(11): 950-958, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26624246

RESUMO

AIM: Extracellular signal regulated kinase (ERK)1/2 and ERK5 are key kinases of the signalling pathways involved in various cellular responses to kidney injury; however, the mechanistic links between those kinase and renin-angiotensin system (RAS) activations in glomerulonephritis (GN) have not been fully elucidated. In this study, we sought to clarify the potential roles of ERK1/2 and ERK5 via RAS activation in the pathogenesis of GN. METHODS: A rat model of progressive GN was induced by anti-glomerular basement membrane (GBM) injection and the signal transduction pathway in angiotensin II (Ang II)-induced glomerular pathologic alterations were investigated in primary cultured mesangial cells (MCs). RESULTS: Rats developed typical cellular crescents in glomeruli on day 7 that progressed to severe fibrocellular crescents and glomerulosclerosis on day 28. Strong expression of phospho-ERK1/2 was observed on day 7 and phospho-ERK5 expression was markedly increased on day 28 of GN. An angiotensin II type 1 receptor blocker (ARB) suppressed those augmentations. Moreover, ARB treatment attenuated the increases in macrophage infiltration and PCNA-positive cells observed on day 7 in GN rats, as well as the increase in collagen type 1 expression on day 28. Consistently, MCs stimulated by Ang II showed significant increases in proliferation and the expression of MCP-1 and collagen type 1. Interestingly, while the ERK1/2 inhibitor PD98059 abolished the elevations in MCP-1 expression and cell proliferation, the ERK5 inhibitor BIX02189 abrogated the elevation in collagen type 1 expression. CONCLUSION: Altogether, these data suggest that ERK1/2 regulates acute inflammatory reactions, while ERK5 promotes the development of RAS-induced chronic glomerular fibrosis activation in GN.


Assuntos
Angiotensina II/metabolismo , Mesângio Glomerular/metabolismo , Glomerulonefrite , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Fibrose/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Inflamação/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
3.
PLoS One ; 10(4): e0122773, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25835392

RESUMO

Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor (TGF)-ß1-inducible focal adhesion protein. We previously demonstrated that Hic-5 was localized in mesangial cells and its expression was associated with glomerular cell proliferation and matrix expansion in human and rat glomerulonephritis (GN). In the present study, we first assessed the role of Hic-5 in mesangioproliferative GN by injecting Habu venom into heminephrectomized wild type (Hic-5+/+) and Hic-5-deficient (Hic-5-/-) mice. Hic-5+/+ GN mice exhibited glomerular cell proliferation on day 7. Surprisingly, glomerular cell number and Ki-67-positive cells in Hic-5-/- GN mice were significantly greater than those in Hic-5+/+ GN mice on day 7, although the number of glomerular apoptotic cells and the expression of growth factors (platelet-derived growth factor-BB and TGF-ß1) and their receptors were similarly increased in both Hic-5+/+ and Hic-5-/- GN mice. In culture experiments, proliferation assays showed that platelet-derived growth factor-BB and TGF-ß1 enhanced the proliferation of Hic-5-/- mesangial cells compared with Hic-5+/+ mesangial cells. In addition, mitogenic regulation by Hic-5 was associated with altered and coordinated expression of cell cycle-related proteins including cyclin D1 and p21. The present results suggest that Hic-5 might regulate mesangial cell proliferation in proliferative GN in mice. In conclusion, modulation of Hic-5 expression might have a potential to prevent mesangial cell proliferation in the acute mitogenic phase of glomerulonephritis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mesângio Glomerular/metabolismo , Glomerulonefrite/genética , Proteínas com Domínio LIM/metabolismo , Células Mesangiais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Becaplermina , Venenos de Crotalídeos/toxicidade , Ciclina D1/genética , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/farmacologia , Feminino , Regulação da Expressão Gênica , Mesângio Glomerular/efeitos dos fármacos , Mesângio Glomerular/patologia , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/farmacologia , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Camundongos , Camundongos Knockout , Nefrectomia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-sis/genética , Proteínas Proto-Oncogênicas c-sis/metabolismo , Proteínas Proto-Oncogênicas c-sis/farmacologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Trimeresurus/metabolismo
4.
Pediatr Nephrol ; 30(6): 975-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25523477

RESUMO

BACKGROUND: Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. METHODS: We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-ß) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-ß in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. RESULTS: Although there was no change in plasma AGT levels, UAGT and TGF-ß levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-ß, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-ß in renal tissues. CONCLUSIONS: These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinogênio/urina , Glomerulonefrite por IGA/tratamento farmacológico , Rim/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Adolescente , Angiotensina II/sangue , Angiotensina II/urina , Angiotensinogênio/sangue , Biomarcadores/sangue , Biomarcadores/urina , Biópsia , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/urina , Humanos , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Valor Preditivo dos Testes , Fatores de Tempo , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/urina , Resultado do Tratamento , Urinálise
5.
Am J Nephrol ; 38(5): 355-67, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24158104

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) 2 is a homolog of ACE and is thought to be a potent counter-regulator against ACE activity. However, the role of ACE2 has not been investigated in pediatric patients with IgA nephropathy (IgAN). This study was performed to examine the relationship between ACE2 expression and the development of pediatric IgAN. METHODS: We performed immunohistochemical analysis of ACE2 and ACE in 39 patients with pediatric IgAN and 14 patients with minor glomerular abnormalities, and elucidated the effects of various cytokines on ACE2 expression in cultured human mesangial cells. RESULTS: ACE2 expression levels in glomeruli and tubules were positively correlated with the mesangial hypercellularity score, while ACE expression levels in glomeruli and tubules are not. Multiple regression analysis showed that the mesangial hypercellularity score correlated with the ACE2 expression level in glomeruli and the urinary protein-creatinine ratio. In IgAN patients not treated with a renin-angiotensin system blocker, ACE2 expression levels in glomeruli were significantly increased compared to patients with minor glomerular abnormalities. IgAN patients treated with a renin-angiotensin system blocker did not show this increase in ACE2 expression. Furthermore, cultured human MC showed increased ACE2 mRNA and protein after treatment with IL-1ß, a pro-inflammatory cytokine in IgAN. In fact, glomerular expressions of IL-1ß were remarkably increased in patients with IgAN. CONCLUSION: These data indicate that ACE2 expression in glomeruli is associated with mesangial hypercellularity in early lesions of pediatric IgAN.


Assuntos
Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/enzimologia , Glomérulos Renais/enzimologia , Peptidil Dipeptidase A/metabolismo , Adolescente , Enzima de Conversão de Angiotensina 2 , Biópsia , Células Cultivadas , Criança , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Glomérulos Renais/metabolismo , Masculino , Células Mesangiais/enzimologia , RNA Mensageiro/metabolismo , Análise de Regressão , Sistema Renina-Angiotensina
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