RESUMO
The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.
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Podocyte expression of fibroblast specific protein 1 (FSP1) is observed in various types of human glomerulonephritis. Considering that FSP1 is secreted extracellularly and has been shown to have multiple biological effects on distant cells, we postulated that secreted FSP1 from podocytes might impact renal tubules. Our RNA microarray analysis in a tubular epithelial cell line (mProx) revealed that FSP1 induced the expression of heme oxygenase 1, sequestosome 1, solute carrier family 7, member 11, and cystathionine gamma-lyase, all of which are associated with nuclear factor erythroid 2-related factor (Nrf2) activation. Therefore, FSP1 is likely to exert cytoprotective effects through Nrf2-induced antioxidant activity. Moreover, in mProx, FSP1 facilitated Nrf2 translocation to the nucleus, increased levels of reduced glutathione, inhibited the production of reactive oxygen species (ROS), and reduced cisplatin-induced cell death. FSP1 also ameliorated acute tubular injury in mice with cisplatin nephrotoxicity, which is a representative model of ROS-mediated tissue injury. Similarly, in transgenic mice that express FSP1 specifically in podocytes, tubular injury associated with cisplatin nephrotoxicity was also mitigated. Extracellular FSP1 secreted from podocytes acts on downstream tubular cells, exerting renoprotective effects through Nrf2-mediated antioxidant activity. Consequently, podocytes and tubular epithelial cells have a remote communication network to limit injury.
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Antioxidantes , Fator 2 Relacionado a NF-E2 , Humanos , Camundongos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Cisplatino/farmacologia , Cisplatino/metabolismo , Estresse Oxidativo , Heme Oxigenase-1/metabolismoRESUMO
OBJECTIVES: LN comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions. METHODS: MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice [wild type (WT)] to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analysed by quantitative real-time PCR and IF. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc. RESULTS: 2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5 and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68 -positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5 and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1 and CCR2. When 2B11.3 was injected, CCR2-/- and CCR5-/-, but not CX3CR1-/-, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration and improved serum blood urea nitrogen levels. Only CCR2-/- mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum blood urea nitrogen levels. CONCLUSION: CCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in LN. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.
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Nefropatias , Nefrite Lúpica , Receptores CCR2 , Receptores CCR5 , Animais , Anticorpos Monoclonais , Células Endoteliais/metabolismo , Imunoglobulina G/metabolismo , Nefropatias/metabolismo , Nefrite Lúpica/patologia , Macrófagos/metabolismo , Maraviroc/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismoRESUMO
Focal segmental glomerulosclerosis (FSGS) is a commonly occurring cause of steroid-resistant nephrotic syndrome and frequently progresses to renal failure. Podocyte epithelial-mesenchymal transition (EMT) is thought to induce podocyte detachment in glomerular diseases, and severe degeneration and shedding of glomerular podocytes plays a major role in the progression of FSGS. We showed that fibroblast specific protein 1 (FSP1), an EMT marker, is strongly expressed in podocytes of FSGS patients, but the significance of podocyte expression of FSP1 to the pathophysiology of FSGS remained unclear. Here, we investigated FSP1 expression in podocytes from mice with adriamycin (ADR)-induced nephropathy, a murine model of FSGS. The number of FSP1-positive (FSP1+) podocytes was increased in ADR-treated mice and positively correlated with the degree of proteinuria and glomerulosclerosis in ADR-treated mice. ADR-induced FSGS and the attendant proteinuria were significantly ameliorated in FSP1 knockout mice as compared to wild type mice. These findings indicate that podocyte expression of FSP1 plays a crucial role in the pathogenesis of FSGS, which makes FSP1 a potential target for treatment of FSGS.
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Doxorrubicina , Glomerulonefrite/induzido quimicamente , Proteína A4 de Ligação a Cálcio da Família S100/genética , Animais , Progressão da Doença , Expressão Gênica , Glomerulonefrite/genética , Glomerulonefrite/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Podócitos/patologia , Proteína A4 de Ligação a Cálcio da Família S100/análiseRESUMO
BACKGROUND: Giant cell tumor of tendon sheath (GCTTS) is a benign soft-tissue tumor that occurs predominantly in the fingers, with the capacity for local recurrence. The cytogenetic hallmark of GCTTS is the presence of 1p13 rearrangement. Several chromosomal segments have been recognized as translocation partners to 1p13. Herein, we describe a novel cytogenetic finding of GCTTS arising in the right thumb of a 71-year-old man. CASE REPORT: Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Magnetic resonance imaging demonstrated a nodular mass with reduced signal intensity on both T1- and T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images showed intense heterogeneous enhancement of the mass. After a needle biopsy, complete excision was performed. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy cells, and inflammatory cells. Cytogenetic analysis revealed a reciprocal t(1;1)(p13;p34) translocation as the sole structural aberration. CONCLUSION: To the best of our knowledge, this is the first report of this tumor with t(1;1)(p13;p34).
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Cromossomos Humanos Par 1 , Tumor de Células Gigantes de Bainha Tendinosa/genética , Translocação Genética , Idoso , Biópsia por Agulha , Tumor de Células Gigantes de Bainha Tendinosa/diagnóstico por imagem , Tumor de Células Gigantes de Bainha Tendinosa/patologia , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND: Erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients with chronic kidney disease, enabling maintenance of stable hemoglobin levels and eliminating the need for multiple transfusions. Epoetin-beta pegol (C.E.R.A.) is a continuous erythropoietin receptor activator created by integrating a large methoxy-polyethylene-glycol-polymer chain into the erythropoietin molecule, which provides it with a longer half-life. On rare occasions, cases of antibody-mediated pure red cell aplasia (PRCA) related to ESAs are reported. They are characterized by abrupt onset of severe transfusion-dependent anemia, despite ESA therapy. We herein report a case of antibody-mediated PRCA in a dialysis patient receiving C.E.R.A. CASE PRESENTATION: A 44-year-old man with end-stage renal failure had been receiving continuous ambulatory peritoneal dialysis for 2 years. C.E.R.A. was administered subcutaneously as a sole ESA once a month at the hospital since 4 years ago for the treatment of renal anemia and his hemoglobin level was well controlled at 12 g/dl. From 10 months before diagnosis, however, his hemoglobin level suddenly declined, necessitating frequent transfusions. Based on the results of a bone marrow examination and detection of anti-C.E.R.A. antibodies, the patient was diagnosed with antibody-mediated PRCA. After successful elimination of the antibodies using oral prednisolone plus cyclosporine, the patient was re-administrated C.E.R.A. intravenously, as there are few reports of antibody-mediated PRCA related to ESA using that administration route. He responded to the C.E.R.A., and his anemia dramatically improved, eliminating the need for blood transfusions. CONCLUSIONS: This is the first reported case of recovery from an antibody-mediated PRCA with C.E.R.A. after its re-administration following a reversal of the antibody. It has been suggested that the additional large pegylation chain makes C.E.R.A. less likely to trigger antibody generation than other ESAs. Following successful treatment of antibody-mediated PRCA using immunosuppressive therapy, C.E.R.A. can be re-administered intravenously to treat renal anemia.
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Anemia/tratamento farmacológico , Anticorpos/imunologia , Eritropoetina/imunologia , Hematínicos/imunologia , Falência Renal Crônica/terapia , Aplasia Pura de Série Vermelha/imunologia , Adulto , Anemia/etiologia , Ciclosporina/uso terapêutico , Eritropoetina/administração & dosagem , Glucocorticoides/uso terapêutico , Hematínicos/administração & dosagem , Humanos , Imunossupressores/uso terapêutico , Injeções Intravenosas , Injeções Subcutâneas , Falência Renal Crônica/complicações , Masculino , Polietilenoglicóis/administração & dosagem , Prednisolona/uso terapêutico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Diálise RenalRESUMO
A 62-year-old man visited our hospital with a mild sore throat, high-grade fever, and clavicular pain. Seven years earlier, he had been diagnosed with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. His clavicles were tender and remarkably swollen. Also noted was marked pitting edema in the lower extremities and pustulosis on the palms and soles of the feet. Laboratory studies on admission showed an elevated white cell count (23,400/µl) and serum C-reactive protein level (24.4 mg/dl). Urinalysis revealed proteinuria (2+) and occult blood (3+) with numerous dysmorphic red blood cells and hyalin casts. The patient was diagnosed with recurrence of his SAPHO syndrome and started on oral glucocorticoid therapy. By day 9 after admission, he had gained 16 kg in body weight, and his proteinuria (6.4 g/day) and serum creatinine level (2.3 mg/dl) were elevated. Renal biopsy revealed mesangial proliferative glomerulonephritis with deposition of IgA and C3 in the mesangial area and along the capillary walls. The patient was diagnosed with IgA nephropathy accompanied by nephrotic syndrome. With oral prednisolone therapy, his fever, clavicular pain, and proteinuria were gradually relieved. The clinical course in this case suggests the onset of nephrotic syndrome with IgA nephropathy was associated with the recurrence of the patient's SAPHO. To our knowledge, this is the first reported case of SAPHO-associated IgA nephropathy.
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BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron-transporting factor which possesses various activities such as amelioration of kidney injury and host defense against pathogens. Its circulating concentrations are elevated in acute and chronic kidney diseases and show a positive correlation with poor renal outcome and mortality, but its clinical significance in maintenance hemodialysis (HD) patients remains elusive. METHODS: Serum NGAL levels were determined by enzyme-linked immunosorbent assay in out-patient, Japanese HD subjects. Their correlation to laboratory findings and morbidity (as development of severe infection or serum albumin reduction) was investigated using linear regression analysis and χ2 test. RESULTS: Pre-dialysis serum NGAL levels in HD patients were elevated by 13-fold compared to healthy subjects (n=8, P<0.001). In a cross-sectional study of 139 cases, serum NGAL concentrations were determined independently by % creatinine generation rate (an indicator of muscle mass, standardized coefficient ß=0.40, P<0.001), peripheral blood neutrophil count (ß=0.38, P<0.001) and anion gap (which likely reflects dietary protein intake, ß=0.16, P<0.05). Iron administration to anemic HD patients caused marked elevation of peripheral blood hemoglobin, serum ferritin and iron-regulatory hormone hepcidin-25 levels, but NGAL levels were not affected. In a prospective study of 87 cases, increase in serum albumin levels a year later was positively associated to baseline NGAL levels by univariate analysis (r=0.36, P<0.01). Furthermore, within a year, patients with the lowest NGAL tertile showed significantly increased risk for marked decline in serum albumin levels (≥0.4 g/dl; odds ratio 5.5, 95% confidence interval 1.5-20.3, P<0.05) and tendency of increased occurrence of severe infection requiring admission (odds ratio 3.1, not significant) compared to the middle and highest tertiles. CONCLUSION: Low serum NGAL levels appear to be associated with current malnutrition and also its progressive worsening in maintenance HD patients.
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Lipocalinas/sangue , Desnutrição/sangue , Proteínas Proto-Oncogênicas/sangue , Diálise Renal , Proteínas de Fase Aguda , Fatores Etários , Idoso , Aorta/metabolismo , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Inflamação/patologia , Ferro/administração & dosagem , Ferro/farmacologia , Modelos Lineares , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Veias Renais/metabolismo , Albumina Sérica/metabolismoRESUMO
Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (nâ=â236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels.
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Calcitriol/sangue , Glucuronidase/metabolismo , Fosfatos/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Expressão Gênica , Taxa de Filtração Glomerular , Glucuronidase/genética , Células HEK293 , Humanos , Rim/metabolismo , Rim/fisiopatologia , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Fosfatos/urina , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Adulto JovemRESUMO
OBJECTIVE: To examine the role played by E-selectin in bystander IgM-mediated modification of glomerular lesions in experimental lupus nephritis. METHODS: Experimental lupus SCID mice were induced by an intraperitoneal injection of clone 7B6.8, which was derived from a MRL/lpr mouse and shown to induce wire-loop type glomerular lesions. Mice were subsequently administered clone Sp6, a non-nephritogenic IgM antibody- producing hybridoma. E-selectin expression was then evaluated in glomeruli showing histopathological conversion of lesions from wire-loop-like to a cell-proliferative form. We also investigated the effects of a circulating soluble form of E-selectin (sE-selectin) on the modification of glomerular lesions in this lupus model. RESULTS: In experimental lupus mice, glomerular E-selectin expression significantly increased during the conversion from wire-loop-like glomerular lesions to a cell-proliferative type mediated by a non-nephritogenic bystander IgM antibody in presence of a nephritogenic antibody. Intraglomerular infiltration of CD68 + macrophages correlated significantly with the glomerular level of E-selectin expression. In addition, overexpression of circulating sE-selectin significantly suppressed conversion to cell-proliferative glomerular lesions and glomerular macrophage infiltration in these lupus model mice. CONCLUSIONS: The histopathological modification of lupus nephritis by non-nephritogenic bystander IgM antibodies is associated in part with glomerular E-selectin expression.
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Selectina E/metabolismo , Imunoglobulina M/imunologia , Glomérulos Renais/metabolismo , Nefrite Lúpica/metabolismo , Animais , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos SCIDRESUMO
Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.
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Aterosclerose/etiologia , Insuficiência Renal Crônica/complicações , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Heparina/administração & dosagem , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Estresse Oxidativo , Fator de Crescimento Placentário , Valor Preditivo dos Testes , Proteínas da Gravidez/sangue , Prognóstico , Isoformas de Proteínas , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
A 69-year-old postmenopausal woman who was prescribed anastrozole for 10 months after surgical removal of her breast cancer, was referred to our hospital for acute renal failure. Because it was possible that her renal failure was related to her treatment with anastrozole, the treatment was immediately discontinued. After renal biopsy was performed to examine her renal failure, she was diagnosed as crescentic glomerulonephritis, probably related with the treatment of anastrozole. Twenty mg of oral prednisolone was administered daily after methylprednisolone pulse therapy(500 mg/day intravenous administration for three days). Her renal dysfunction was gradually improved. Renal dysfunction was considered to be a rare complication of anastrozole. Patients who are prescribed anastrozole should be watched carefully for the development of renal dysfunction.
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Antineoplásicos Hormonais/efeitos adversos , Glomerulonefrite/induzido quimicamente , Nitrilas/efeitos adversos , Triazóis/efeitos adversos , Administração Oral , Idoso , Anastrozol , Antineoplásicos Hormonais/administração & dosagem , Biópsia , Neoplasias da Mama/terapia , Quimiorradioterapia , Terapia Combinada , Feminino , Glomerulonefrite/patologia , Humanos , Nitrilas/administração & dosagem , Triazóis/administração & dosagemRESUMO
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes inflammatory tissue damage, including lupus nephritis and vasculitis. Local generation of adhesion molecules and expression of their ligands on inflammatory cells appears to contribute to the progression of SLE. We found significantly increased E-selectin expression in the glomeruli and renal interstitial microvasculature of MRL/MpJ-lpr/lpr (MRL/lpr) lupus model mice. This was accompanied with infiltration of inflammatory cells, especially macrophages and CD8(+) T cells. Similarly, in 21 patients with proliferative lupus nephritis, there was a significant correlation between renal E-selectin levels and macrophage and CD8(+) T cell infiltration in the affected kidneys. By contrast, in transgenic MRL/lpr mice exhibiting elevated levels of circulating soluble E-selectin (sE-selectin) protein, which competitively inhibits E- and P-selectin-mediated extravasation of inflammatory cells, the progression of lupus nephritis and vasculitis was significantly suppressed and survival was significantly prolonged. This improvement was accompanied by significant reductions in renal infiltration by macrophages and CD8(+) T cells. These results suggest that E-selectin plays a crucial role in lupus nephritis and vasculitis by mediating renal infiltration of inflammatory cells, and that because it inhibits this process, sE-selectin could potentially serve as an effective treatment for lupus nephritis and vasculitis.
RESUMO
A 69-year-old man with a history of hypertension was admitted to our hospital because of proteinuria, renal dysfunction, and both purpura and edema in the lower extremities. Laboratory data on admission revealed proteinuria (3.4 g/day), microscopic hematuria (3+), and renal dysfunction (serum creatinine 1.47 mg/dL). In the renal biopsy, all glomeruli showed mild mesangial proliferation. A few glomeruli showed mild segmental endocapillary proliferation. Crescent was not found in any glomeruli. Immunofluorescent study revealed the deposition of IgA and C3 in the mesangial area. In addition, jagged-edged angular cholesterol clefts of atheromatous emboli were seen in a small artery with tubular atrophy and fibrosis. He was diagnosed as Henoch-Schonlein purpura nephritis accompanied by idiopathic cholesterol crystal embolism, because he previously had not undergone any cardiac procedures (e. g., percutaneous coronary intervention and coronary artery bypass grafting) and anticoagulating therapy. Oral prednisolone (40 mg/day) effectively decreased proteinuria and improved his renal dysfunction. In this case, renal dysfunction may be related to the ischemic interstitial damage caused by cholesterol crystal embolism, as well as purpura nephritis.
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Embolia de Colesterol/complicações , Vasculite por IgA/etiologia , Nefrite/etiologia , Idoso , Embolia de Colesterol/tratamento farmacológico , Fluorbenzenos/administração & dosagem , Humanos , Vasculite por IgA/tratamento farmacológico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Nefrite/tratamento farmacológico , Nefrite/patologia , Prednisolona/administração & dosagem , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Pirimidinas/administração & dosagem , Rosuvastatina Cálcica , Sulfonamidas/administração & dosagemRESUMO
Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease. Renal α-Klotho expression was significantly lower and urinary calcium excretion (UCa/UCr) significantly higher in diabetic nephropathy than in IgA nephropathy or minimal change disease. Multiple regression analyses indicated that α-Klotho mRNA was inversely correlated with calcium excretion. We next measured these parameters in a mouse model of streptozotocin (STZ)-induced diabetic nephropathy, characterized by glomerular hyperfiltration, as seen in early diabetic nephropathy. We also confirmed a reduction of renal α-Klotho mRNA down to almost 50% and enhanced calcium excretion in mice with STZ-induced diabetic nephropathy in comparison with nondiabetic mice. Hypercalciuria was exacerbated in heterozygous α-Klotho knockout mice in comparison with wild-type mice, each with STZ-induced diabetic nephropathy. Thus, α-Klotho expression was decreased in distal convoluted tubules in diabetic nephropathy in humans and mice. Renal loss of α-Klotho may affect urinary calcium excretion in early diabetic nephropathy.
Assuntos
Cálcio/urina , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Glucuronidase/metabolismo , Hipercalciúria/etiologia , Túbulos Renais Distais/metabolismo , Receptores de Superfície Celular/metabolismo , Adulto , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/urina , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/urina , Regulação para Baixo , Glucuronidase/genética , Células HEK293 , Heterozigoto , Humanos , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/urina , Proteínas Klotho , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Fatores de Tempo , Transfecção , Adulto JovemRESUMO
Fibroblast-specific protein 1 (FSP1)-expressing cells accumulate in damaged kidneys, but whether urinary FSP1 could serve as a biomarker of active renal injury is unknown. We measured urinary FSP1 in 147 patients with various types of glomerular disease using ELISA. Patients with crescentic GN, with or without antinuclear cytoplasmic antibody-associated GN, exhibited elevated levels of urinary FSP1. This assay had a sensitivity of 91.7% and a specificity of 90.2% for crescentic GN in this sample of patients. Moreover, we found that urinary FSP1 became undetectable after successful treatment, suggesting the possible use of FSP1 levels to monitor disease activity over time. Urinary FSP1 levels correlated positively with the number of FSP1-positive glomerular cells, predominantly podocytes and cellular crescents, the likely source of urinary FSP1. Even in patients without crescent formation, patients with high levels of urinary FSP1 had large numbers of FSP1-positive podocytes. Taken together, these data suggest the potential use of urinary FSP1 to screen for active and ongoing glomerular damage, such as the formation of cellular crescents.
Assuntos
Proteínas de Ligação ao Cálcio/urina , Glomerulonefrite/diagnóstico , Biomarcadores , Proteínas de Ligação ao Cálcio/sangue , Creatinina/sangue , Ensaio de Imunoadsorção Enzimática , Glomerulonefrite/urina , Humanos , Proteína A4 de Ligação a Cálcio da Família S100 , Sensibilidade e EspecificidadeRESUMO
BACKGROUNDS/AIMS: We previously reported that fibroblast-specific protein 1 (FSP1) is a marker of epithelial-mesenchymal transition (EMT) in tubulointerstitial fibrosis. The EMT-like changes observed in podocytes are reportedly associated with podocyte detachment which may cause focal glomerulosclerosis. METHODS: In cross-sectional studies, we analyzed podocyte expression of FSP1 immunohistochemically using renal biopsy specimens from 31 patients with focal segmental glomerulosclerosis (FSGS) and 39 patients with minimal change disease (MCD). We also semiquantitatively analyzed glomerular expression of FSP1 mRNA using laser capture microdissection and real-time PCR. RESULTS: We found that FSP1 was localized to podocytes in both FSGS and MCD patients; however, the number of FSP1(+) podocytes per glomerular profile was significantly higher in patients with FSGS than in those with MCD, and there was a corresponding difference in the levels of FSP1 mRNA. FSP1(+) podocyte counts per glomerular profile in FSGS patients correlated significantly with the prevalence of glomerulosclerosis and the extent of interstitial type-I collagen-positive areas. CONCLUSION: Taken together, these data suggest that podocyte expression of FSP1 could shed light on the potential linkage between EMT-like changes, detachment of podocytes from the glomerular basal membrane and the pathophysiology underlying FSGS.
Assuntos
Proteínas de Ligação ao Cálcio/biossíntese , Glomerulosclerose Segmentar e Focal/metabolismo , Nefrose Lipoide/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores , Biópsia , Proteínas de Ligação ao Cálcio/genética , Adesão Celular , Contagem de Células , Transição Epitelial-Mesenquimal , Feminino , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Nefrose Lipoide/genética , Nefrose Lipoide/patologia , Nefrose Lipoide/fisiopatologia , Podócitos/química , Podócitos/metabolismo , RNA Mensageiro/análise , Proteína A4 de Ligação a Cálcio da Família S100 , Adulto JovemRESUMO
BACKGROUND: Alpha-Klotho (alphaKl) regulates mineral metabolism such as calcium ion (Ca(2+)) and inorganic phosphate (Pi) in circulation. Defects in mice result in clinical features resembling disorders found in human aging. Although the importance of transmembrane-type alphaKl has been demonstrated, less is known regarding the physiological importance of soluble-type alphaKl (salphaKl) in circulation. OBJECTIVES: The aims of this study were: (1) to establish a sandwich ELISA system enabling detection of circulating serum salphaKl, and (2) to determine reference values for salphaKl serum levels and relationship to indices of renal function, mineral metabolism, age and sex in healthy subjects. RESULTS: We successively developed an ELISA to measure serum salphaKl in healthy volunteers (n=142, males 66) of ages (61.1+/-18.5year). The levels (mean+/-SD) in these healthy control adults were as follows: total calcium (Ca; 9.46+/-0.41mg/dL), Pi (3.63+/-0.51mg/dL), blood urea nitrogen (BUN; 15.7+/-4.3mg/dL), creatinine (Cre; 0.69+/-0.14mg/dL), 1,25 dihydroxyvitamin D (1,25(OH)(2)D; 54.8+/-17.7pg/mL), intact parathyroid hormone (iPTH; 49.2+/-20.6pg/mL), calcitonin (26.0+/-12.3pg/mL) and intact fibroblast growth factor (FGF23; 43.8+/-17.6pg/mL). Serum levels of salphaKl ranged from 239 to 1266pg/mL (mean+/-SD; 562+/-146pg/mL) in normal adults. Although salphaKl levels were not modified by gender or indices of mineral metabolism, salphaKl levels were inversely related to Cre and age. However, salphaKl levels in normal children (n=39, males 23, mean+/-SD; 7.1+/-4.8years) were significantly higher (mean+/-SD; 952+/-282pg/mL) than those in adults (mean+/-SD; 562+/-146, P<0.001). A multivariate linear regression analysis including children and adults in this study demonstrated that salphaKl correlated negatively with age and Ca, and positively with Pi. Finally, we measured a serum salphaKl from a patient with severe tumoral calcinosis derived from a homozygous missense mutation of alpha-klotho gene. In this patient, salphaKl level was notably lower than those of age-matched controls. CONCLUSION: We established a detection system to measure human serum salphaKl for the first time. Age, Ca and Pi seem to influence serum salphaKl levels in a normal population. This detection system should be an excellent tool for investigating salphaKl functions in mineral metabolism.
Assuntos
Envelhecimento/sangue , Ensaio de Imunoadsorção Enzimática , Glucuronidase/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais/imunologia , Cálcio/sangue , Criança , Feminino , Fator de Crescimento de Fibroblastos 23 , Glucuronidase/genética , Glucuronidase/imunologia , Humanos , Proteínas Klotho , Masculino , Camundongos , Pessoa de Meia-Idade , MutaçãoRESUMO
Fractalkine (Fkn) is expressed on injured endothelial cells and is a membrane-bound chemokine that attracts cells expressing its receptor, CX3CR1, including CD16(+) monocytes (CD16(+) Mos). To clarify the role played by Fkn in the development of glomerular lesions in lupus nephritis, we examined Fkn expression and CD16(+) Mo accumulation induced in experimental C.B-17/Inc-scid/scid (SCID) lupus model mice by injection of IgG(3)-producing hybridoma clones obtained from MRL/lpr mice. Glomerular Fkn expression and accumulation of CD16(+) Mos were semiquantitatively evaluated using laser capture microdissection and real-time PCR. Injection of the 2B11.3 and 7B6.8 clones induced formation of glomerular proliferative and wire-loop lesions, respectively. Immunohistological analysis of the localization of Fkn and CD16(+) Mos revealed that Fkn expression and CD16(+) Mo accumulation were markedly elevated in glomerular lesions induced by 2B11.3, whereas no elevation was detected in those induced by 7B6.8. In addition, to examine the contribution of glomerular Fkn to the development of proliferative lesions, L cells producing an Fkn antagonist (Fkn-AT) were transplanted into SCID mice exhibiting proliferative lupus nephritis (DPLN) induced by 2B11.3. Notably, transplantation of the Fkn-AT-producing cells was functionally and histologically protective against this DPLN. Taken together, our findings suggest that Fkn and CD16(+) Mo accumulation are partially associated with the severity and diversity of histology of lupus nephritis.
Assuntos
Proliferação de Células , Quimiocina CX3CL1/metabolismo , Glomérulos Renais/imunologia , Nefrite Lúpica/imunologia , Monócitos/imunologia , Receptores de IgG/metabolismo , Animais , Quimiocina CX3CL1/genética , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Células Endoteliais/imunologia , Fibroblastos/imunologia , Fibroblastos/transplante , Humanos , Hibridomas , Imunoglobulina G/imunologia , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Glomérulos Renais/patologia , Células L , Nefrite Lúpica/patologia , Nefrite Lúpica/prevenção & controle , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos SCID , Microdissecção , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Transfecção , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A 61-year-old woman with a continuous left temporal headache and a fever of 39°C for about one month was admitted to our hospital. The physical examination was not remarkable, except for slight tenderness of the left temporal side of her head. Laboratory data on admission revealed an increase of leucocytes (9,700/µl), blood platelets (59.4×10(4)/µl), and serum c-reactive protein (CRP) (10.9 mg/dl). The erythrocyte sedimentation rate (ESR) was also elevated (88 mm/1 h). After gallium scintigraphy, a gallium-67 uptake was weakly detected at the left temporal side of her head. However, after FDG-PET examination, a high FDG uptake was detected in her temporal artery, abdominal aorta, and bilateral femoral arteries. Moreover, Doppler sonography showed a hypoechoic halo around her left temporal artery. After treatment with oral prednisolone (40 mg/day), her headache disappeared and her serum CRP level returned to normal. Finally, the patient had pathological temporal arteritis proven by a biopsy. It is difficult to make an early diagnosis of temporal arteritis if the dilatation or swelling of the temporal arteries is not present. FDG-PET is considered a useful examination not only for the exploration of tumors, but also for the evaluation of the inflammation of large vessels.