Publications (13) View all
-
Article: Abnormal conformation and impaired degradation of NETs induced by propylthiouracil: Implication of disordered NETs in MPO-ANCA-associated vasculitis.
[show abstract] [hide abstract]
ABSTRACT: OBJECTIVE: Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies demonstrate that impaired regulation of NETs could trigger autoimmune response to NETs. Propylthiouracil (PTU), an anti-thyroid drug, is known to have a risk to induce MPO-ANCA production and MPO-ANCA-associated vasculitis (MPO-AAV). The aim of this study is to clarify the mechanism of MPO-ANCA production, using the PTU-induced MPO-AAV model. METHODS: NETs were induced by treatment of neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU can influence the NETs formation induced by PMA and degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether the NETs generated by PMA with PTU can induce MPO-ANCA and MPO-AAV in vivo. RESULTS: When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO-ANCA and developed pulmonary capillaritis. When rats were given oral administration of PTU with intra-peritoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO-ANCA production in the serum. CONCLUSION: Abnormal conformation and impaired degradation of NETs induced by PTU were involved in the pathogenesis of PTU-induced MPO-ANCA production and MPO-AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO-AAV.Arthritis & Rheumatism 07/2012; · 7.87 Impact Factor -
Article: Renal disease progression in autosomal dominant polycystic kidney disease.
[show abstract] [hide abstract]
ABSTRACT: Autosomal dominant polycystic kidney disease is a lifelong progressive disorder. However, how age, blood pressure, and stage of chronic kidney disease (CKD) affect the rate of kidney function deterioration is not clearly understood. In this long-term observational case study up to 13.9 years (median observation period for slope was 3.3 years), serum creatinine was serially measured in 255 mostly adult patients. The glomerular filtration rate was estimated (eGFR) using a modified Modification of Diet in Renal Disease Study method. The total kidney volume (TKV) has been measured in 86 patients at one center since 2006. As age increased, eGFR declined significantly (P < 0.0001), but the annual rate of decline of eGFR did not correlate with age or initially measured eGFR. In patients with CKD stage 1, eGFR declined at a rate which was not significantly different from other advanced CKD stages. Hypertensive patients had lower eGFR and larger TKV than normotensive patients at a young adult age. The slopes of regression lines of eGFR and TKV in relation to age were not different between high and normal blood pressure groups. The declining rate of eGFR was relatively constant and did not correlate with age or eGFR after adolescence. eGFR was already low in young adult patients with hypertension. As age increased after adolescence, eGFR declined and TKV increased similarly between normal and high blood pressure groups. eGFR starts to decline in patients with normal eGFR, suggesting that the decline starts earlier than previously thought.Clinical and Experimental Nephrology 04/2012; 16(4):622-8. · 1.37 Impact Factor -
Article: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation
[show abstract] [hide abstract]
ABSTRACT: Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.Nature Genetics 06/2011; 43(7):639-647. · 35.53 Impact Factor -
Article: Transplantation-associated thrombotic microangiopathy after steroid pulse therapy for polyserositis related to graft-versus-host disease.
[show abstract] [hide abstract]
ABSTRACT: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a rare but devastating syndrome that occurs in allogeneic hematopoietic stem cell transplant recipients, and is associated with a variety of transplantation-related factors, including conditioning regimens, immunosuppressive agents, graft-versus-host disease (GVHD) and opportunistic infections. TA-TMA has an unfavorable prognosis and responds poorly to conventional treatment including plasma exchange (PE). We present a case of a 37-year-old man with membranous nephropathy (MN) and polyserositis caused by GVHD after hematopoietic stem cell transplantation. He developed TA-TMA after steroid pulse therapy for polyserositis. We treated the patient with PE and mycophenolate mofetil (MMF) after which the TA-TMA successfully improved and the MN underwent complete remission. The present case suggests that corticosteroids with severe GVHD might increase the risk of TA-TMA, and that PE in combination with MMF may be a valuable therapy to improve the prognosis.Clinical and Experimental Nephrology 02/2011; 15(1):179-83. · 1.37 Impact Factor -
Article: Distinct macrophage phenotypes contribute to kidney injury and repair.
[show abstract] [hide abstract]
ABSTRACT: The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.Journal of the American Society of Nephrology 02/2011; 22(2):317-26. · 9.66 Impact Factor
