メタロプロティナーゼによる糸球体メサンギウム基質の代謝調節機構

金沢大学医療技術短期大学部目的:糸球体細胞外基質(ECM)の代謝調節には、メサンギウム細胞(MC)により産生されるECMに加え、その分解酵素であるmetalloproteinase(MMP)やそのinhibitor(TIMP)の関与が大きいものと考えられる.本研究では、種々の刺激に対するMCにおけるMMPsの発現制御機構を明らかにする.結果:摘出腎癌の健常部から精製したヒトMCを、10ng/mlのIL-1-β、TNF-α、PDGFで刺激すると、MMP-2、TIMP、fibronectin(FN)のmRNA転写レベルは、RT-PCRでの検討では増加した.これらの因子とTGF-βを同時に添加するとMMP-2の発現はそれぞれ抑制された.この反応は、サイトカインや増殖因子などの刺激ではMMP-2遺伝子の発現誘導を受けないことが特徴とされている線維芽細胞とは異なるものである.さらに、5mg/mlの少量のFNを添加すると、MMP-2の発現は正常の3-4倍誘導されたが、添加FNが50-100mg/mlと増量するにつれ正常の0.8-0.6倍に低下した.一方、ABC法で検討したヒト腎疾患(IgA腎症、急速進行性糸球体腎炎、糖尿病性腎症など)では、メサンギウム領域にMMP-2が染色され、またin situ hybridizationによってもmRNAの発現が確認された.ラット腎炎(ATS腎炎、1-22-3腎炎、馬杉腎炎)でのMMP-2は、その増殖度合いに応じて発現が確認された.まとめ:間葉系由来細胞であるMCは、線維芽細胞とは異なるMMP-2の発現制御機構を有していることが判明した.この制御機構においては、糸球体腎炎の急性期ではサイトカインや増殖因子はMMP-2発現を誘導して組織障害を修復し、また慢性期ではECM増生は逆にMMP-2発現を抑制して糸球体硬化を進展させることを示唆している.本研究により糸球体硬化の機序にMMP-2が関与していることが明確になった.研究課題/領域番号:05670951, 研究期間(年度):1993出典：研究課題「メタロプロティナーゼによる糸球体メサンギウム基質の代謝調節機構」課題番号05670951（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-05670951/）を加工して作

Anti-interleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman’s disease

We report two cases of multicentric Castleman’s disease (MCD) whose serum hepcidin levels were rapidly down-regulated by administration of tocilizumab, an anti- interleukin 6 (IL-6) receptor antibody. Our results indicate that IL-6-induced hepcidin over-production may be involved in the pathophysiology of microcytic anemia commonly observed in this disease

Prevention of proteinuria by the administration of anti-interleukin 8 antibody in experimental acute immune complex-induced glomerulonephritis

Glomerular infiltration by neutrophils is a hallmark of acute glomerulonephritis. The pathophysiological role of interleukin 8 (IL-8), a potent neutrophil chemotactic cytokine (chemokine), was explored in an animal model of acute immune complex-mediated glomerulonephritis by administering a neutralizing antibody against IL-8. Repeated injection of bovine serum albumin (BSA) into rabbits caused the deposition of immune complexes consisting of BSA and rabbit IgG in glomeruli. Histological analyses revealed a small but significant number of neutrophils in glomeruli and the fusion of epithelial cell foot processes. Concomitantly, urinary levels of protein and albumin increased markedly (3.20 ± 0.97 and 1.39 ± 0.53 mg/h, respectively) compared with those of untreated animals (0.77 ± 0.21 and 0.01 ± 0.01 mg/h, respectively). Anti-IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and dramatically prevented the fusion of epithelial cell foot process. Furthermore, treatment with anti-IL-8 antibody completely normalized the urinary levels of protein and albumin (0.89 ± 0.15 and 0.02 ± 0.01 mg/h, respectively). These results indicated that IL-8 participated in the impairment of renal functions in experimental acute immune complex-mediated glomerulonephritis through activating as well as recruiting neutrophils

99mTc－MAG3による腎機能評価－123I-OIHおよび99mTc－DTPAとの比較－

金沢大学大学院医学系研究

Expression of hepcidin mRNA is uniformly suppressed in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>The present study evaluated the expression of hepcidin mRNA in hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>Samples of cancerous and non-cancerous liver tissue were taken from 40 patients with HCC who underwent hepatectomy. Expression of hepcidin mRNA was evaluated by real-time PCR, and compared in tumors differing in their degree of differentiation, number of tumors, and vessel invasion. Correlations between hepcidin expression and the interval until HCC recurrence, and the serum concentration of hepcidin were evaluated, together with the expression of mRNAs for other iron metabolism molecules, ferroportin and transferrin receptor 2 (Trf2).</p> <p>Results</p> <p>Hepcidin mRNA expression in non-cancerous and cancerous tissues was 1891.8 (32.3–23187.4) and 53.4 (1.9–3185.8), respectively (<it>P </it>< 0.0001). There were no significant differences in hepcidin expression among tumors differing in their degree of differentiation, number of tumors, or vessel invasion. There was no significant correlation between hepcidin expression and the interval until HCC recurrence. The serum concentration of hepcidin-25 was not correlated with hepcidin-mRNA expression. Finally, there were no significant differences in the expression of mRNA for ferroportin and Trf2 between cancerous and non-cancerous tissues.</p> <p>Conclusion</p> <p>Expression of hepcidin mRNA is strikingly suppressed in cancerous, but not in non-cancerous tissues, in patients with HCC, irrespective of ferroportin or Trf2 expression. Uniform suppression of hepcidin may be linked to the development of HCC.</p

Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency

Iron plays the central role in oxygen transport by erythrocytes as a constituent of heme and hemoglobin. The importance of iron and heme is also to be found in their regulatory roles during erythroblast maturation. The transcription factor Bach1 may be involved in their regulatory roles since it is deactivated by direct binding of heme. To address whether Bach1 is involved in the responses of erythroblasts to iron status, low iron conditions that induced severe iron deficiency in mice were established. Under iron deficiency, extensive gene expression changes and mitophagy disorder were induced during maturation of erythroblasts. Bach1−/− mice showed more severe iron deficiency anemia in the developmental phase of mice and a retarded recovery once iron was replenished when compared with wild-type mice. In the absence of Bach1, the expression of globin genes and Hmox1 (encoding heme oxygenase-1) was de-repressed in erythroblasts under iron deficiency, suggesting that Bach1 represses these genes in erythroblasts under iron deficiency to balance the levels of heme and globin. Moreover, an increase in genome-wide DNA methylation was observed in erythroblasts of Bach1−/− mice under iron deficiency. These findings reveal the principle role of iron as a regulator of gene expression in erythroblast maturation and suggest that the iron-heme-Bach1 axis is important for a proper adaptation of erythroblast to iron deficiency to avoid toxic aggregates of non-heme globin

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity

Increased serum hepcidin-25 level and increased tumor expression of hepcidin mRNA are associated with metastasis of renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepcidin has an important role in iron metabolism. We investigated whether hepcidin was involved in renal cell carcinoma (RCC).</p> <p>Methods</p> <p>We measured serum hepcidin-25 levels in 32 patients by liquid chromatograpy (LC)-mass spectrometry (MS)/MS, and assessed hepcidin mRNA expression in paired tumor and non-tumor tissue samples from the surgical specimens of 53 consecutive patients with RCC by real-time reverse transcription polymerase chain reaction.</p> <p>Results</p> <p>The serum hepcidin-25 level was higher in patients with metastatic RCC than nonmetastatic RCC (<it>P </it>< 0.0001), and was positively correlated with the serum interleukin-6 and C-reactive protein levels (<it>P </it>< 0.001). Expression of hepcidin mRNA was lower in tumor tissues than in non-tumor tissues (<it>P </it>< 0.0001). The serum hepcidin-25 level was not correlated with the expression of hepcidin mRNA in the corresponding tumor tissue specimens from 32 patients. Hepcidin mRNA expression in tumor tissue was correlated with metastatic potential, but not with histological differentiation or tumor stage. Kaplan-Meier analysis showed that over expression of hepcidin mRNA was related to shorter overall survival in RCC patients. Univariate analysis (Cox proportional hazards model) showed that the hepcidin mRNA level was an independent prognostic factor for overall survival.</p> <p>Conclusion</p> <p>Our findings suggest that a high serum hepcidin-25 level may indicate the progression of RCC, and that upregulation of hepcidin mRNA expression in tumor tissue may be related to increased metastatic potential.</p

Measurement of serum hepcidin-25 levels as a potential test for diagnosing hemochromatosis and related disorders

石川県立中央病院金沢大学医薬保健研究域医学系Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes. Methods We measured serum iron parameters and hepcidin- 25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE hemochromatosis. Results One patient with HJV hemochromatosis, 2 with TFR2 hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. © Springer 2010