研究者詳細 - 和田　淳

論文 - 和田　淳

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Retroperitoneal Solid Pseudopapillary Tumor Mimicking Adrenal Malignant Tumor in a 67-Year-Old Man. 査読国際誌

Takahiro Ishii, Tomohiro Terasaka, Kenji Nishida, Jun Wada

JCEM case reports 1 ( 4 ) luad090 2023年7月

記述言語：英語

Solid pseudopapillary tumor (SPT) is a low-grade malignant tumor of the pancreas. SPT typically affects women and can occur in ectopic pancreatic region; however, it also occurs rarely in retroperitoneum. The tumor may be bulky at the time of diagnosis since there is no specific clinical manifestation. Here we present an older male case with retroperitoneal SPT. A 67-year-old man consulted for intermittent fever and lumbago. His basal hormonal profile screened out a functional tumor. Computed tomography (CT) showed a gigantic mass in his left adrenal region. A normal left adrenal gland was not identified, and the tumor's feeding artery was recognized as the left adrenal artery by the contrast-enhanced CT. Adrenal malignant tumor was suspected, and tumor resection was performed. The resected tumor size was 15 × 10 × 9 cm. Histologically, epithelial-like cells with round nuclei and a small amount of eosinophilic cytoplasm proliferated in papillary (around the blood vessels) or uniformly solid form. By immunostaining, tumor cells were vimentin, CD56, cytokeratin AE1/AE3, CD10, β-catenin in the nucleus, cyclin D1, and PgR positive. These findings led to the diagnosis of SPT. Although rare, SPT should be considered as a differential diagnosis in cases of a mass arising from the adrenal region.

DOI： 10.1210/jcemcr/luad090

NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease 査読国際誌

Farhad Danesh, Koki Mise, Jianyin Long, Daniel Galvan, Zengchun Ye, Guizhen Fan, Irina Serysheva, Travis Moore, Jun Wada, Paul Schumacker, Benny Chang

Nature communications 15 ( 1 ) 1965 - 1965 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generate diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that conditional male mice with genetic overexpression of Ndufs4 exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping protein STOML2 in linking NDUFS4 with improved cristae morphology. Together, we provide the evidence on the central role of NDUFS4 as a regulator of cristae remodeling and mitochondrial function in kidney podocytes. We propose that targeting NDUFS4 represents a promising approach to slow the progression of DKD.

DOI： 10.21203/rs.3.rs-3070079/v1

Brown Adipose Tissue PPARγ Is Required for the Insulin-Sensitizing Action of Thiazolidinediones. 査読

Yusuke Shibata, Jun Eguchi, Jun Wada

Acta medica Okayama 77 ( 3 ) 243 - 254 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Brown adipose tissue (BAT) plays a critical role in metabolic homeostasis. BAT dysfunction is associated with the development of obesity through an imbalance between energy expenditure and energy intake. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis. However, the roles of PPARγ and thiazolidinediones (TZDs) in the regulation of BAT metabolism remain unclear. TZDs, which are selective PPARγ activators, improve systemic insulin resistance in animals and humans. In the present study, we generated brown adipocyte-specific PPARγ-deficient mice (BATγKO) to examine the in vivo roles of PPARγ and TZDs in BAT metabolism. In electron microscopic examinations, brown adipocyte-specific PPARγ deletion promoted severe whitening of brown fat and morphological alteration of mitochondria. Brown adipocyte-specific PPARγ deletion also reduced mRNA expression of BATselective genes. Although there was no difference in energy expenditure between control and BATγKO mice in calorimetry, norepinephrine-induced thermogenesis was impaired in BATγKO mice. Moreover, pioglitazone treatment improved diet-induced insulin resistance in the control mice but not in the BATγKO mice. These findings suggest that BAT PPARγ is necessary for the maintenance of brown adipocyte function and for the insulin-sensitizing action of TZDs.

DOI： 10.18926/AMO/65489

Effects of Agalsidase Alfa Enzyme Replacement Therapy on Left Ventricular Hypertrophy on Electrocardiogram in a Female Patient with Fabry Disease. 査読

Kazufumi Nakamura, Hiroshi Morita, Yoichi Takaya, Yukihiro Saito, Toru Miyoshi, Hiroshi Morinaga, Hitoshi Sugiyama, Jun Wada, Hiroshi Ito

International heart journal 64 ( 3 ) 502 - 505 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Fabry disease is an X-linked lysosomal storage disorder caused by defective enzyme activity of α-galactosidase A and treated with enzyme replacement therapy (ERT) with recombinant α-galactosidase. ERT reduces left ventricular mass assessed by echocardiography or magnetic resonance imaging. However, electrocardiogram changes during ERT have not been fully elucidated. In the present case, ERT with agalsidase alfa for 4 years decreased QRS voltage and negative T depth along with a reduction of left ventricular mass and wall thickness and improvement of symptoms in a female patient with Fabry disease. Long-term observation of electrocardiogram changes might be useful for determining the efficacy of ERT in this case.

DOI： 10.1536/ihj.22-752

Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps. 査読国際誌

Haruki Watanabe, Masataka Kubo, Akihiko Taniguchi, Yosuke Asano, Sumie Hiramatsu-Asano, Keiji Ohashi, Sonia Zeggar, Eri Katsuyama, Takayuki Katsuyama, Katsue Sunahori-Watanabe, Ken-Ei Sada, Yoshinori Matsumoto, Yasuhiko Yamamoto, Hiroshi Yamamoto, Myoungsun Son, Jun Wada

Clinical immunology (Orlando, Fla.) 250 109317 - 109317 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor that regulates inflammation, cell migration, and cell fate. Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. To understand the function of RAGE in SLE, we generated RAGE-deficient (Ager-/-) lupus-prone mice by backcrossing MRL/MpJ-Faslpr/J (MRL-lpr) mice with Ager-/- C57BL/6 mice. In 18-week-old Ager-/- MRL-lpr, the weights of the spleen and lymph nodes, as well as the frequency of CD3+CD4-CD8- cells, were significantly decreased. Ager-/- MRL-lpr mice had significantly reduced urine albumin/creatinine ratios and markedly improved renal pathological scores. Moreover, neutrophil infiltration and neutrophil extracellular trap formation in the glomerulus were significantly reduced in Ager-/- MRL-lpr. Our study is the first to reveal that RAGE can have a pathologic role in immune cells, particularly neutrophils and T cells, in inflammatory tissues and suggests that the inhibition of RAGE may be a potential therapeutic strategy for SLE.

DOI： 10.1016/j.clim.2023.109317

Association of alcohol consumption and fatigue in SLE: A cross-sectional study from Lupus Registry of Nationwide Institution (LUNA) cohort. 査読国際誌

Yu Katayama, Yoshia Miyawaki, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Keiji Ohashi, Eri Katsuyama, Takayuki Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Nobuyuki Yajima, Yasuhiro Shimojima, Ryusuke Yoshimi, Kunihiro Ichinose, Hiroshi Kajiyama, Michio Fujiwara, Shuzo Sato, Jun Wada

Lupus 32 ( 4 ) 531 - 537 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO). METHODS: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data (n = 580). RESULTS: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [β = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI. CONCLUSIONS: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

DOI： 10.1177/09612033231159471

The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study. 査読国際誌

Yasuhiro Onishi, Haruhito A Uchida, Yohei Maeshima, Yuka Okuyama, Nozomu Otaka, Haruyo Ujike, Keiko Tanaka, Hidemi Takeuchi, Kenji Tsuji, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Morinaga, Masaru Kinomura, Shinji Kitamura, Hitoshi Sugiyama, Kosuke Ota, Keisuke Maruyama, Makoto Hiramatsu, Yoshiyuki Oshiro, Shigeru Morioka, Keiichi Takiue, Kazuyoshi Omori, Masaki Fukushima, Naoyuki Gamou, Hiroshi Hirata, Ryosuke Sato, Hirofumi Makino, Jun Wada

Journal of personalized medicine 13 ( 4 ) 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

DOI： 10.3390/jpm13040582

Serum sCD40L and IL-31 in Association with Early Phase of IgA Nephropathy. 査読国際誌

Keiko Tanaka, Hitoshi Sugiyama, Hiroshi Morinaga, Masashi Kitagawa, Yuzuki Kano, Yasuhiro Onishi, Koki Mise, Katsuyuki Tanabe, Haruhito A Uchida, Jun Wada

Journal of clinical medicine 12 ( 5 ) 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: IgA nephropathy (IgAN) is a major cause of chronic glomerulonephritis worldwide. T cell dysregulation has been reported to contribute to the pathogenesis of IgAN. Methods We measured a broad range of Th1, Th2 and Th17 cytokines in the serum of IgAN patients. We searched for significant cytokines, which were associated with clinical parameters and histological scores in IgAN patients. RESULTS: Among 15 cytokines, the levels of soluble CD40L (sCD40L) and IL-31 were higher in IgAN patients and were significantly associated with a higher estimated glomerular filtration rate (eGFR), a lower urinary protein to creatinine ratio (UPCR), and milder tubulointerstitial lesions (i.e., the early phase of IgAN). Multivariate analysis revealed that serum sCD40L was an independent determinant of a lower UPCR after adjustment for age, eGFR, and mean blood pressure (MBP). CD40, a receptor of sCD40L, has been reported to be upregulated on mesangial cells in IgAN. The sCD40L/CD40 interaction may directly induce inflammation in mesangial areas and may therefore be involved in the development of IgAN. CONCLUSIONS: The present study demonstrated the significance of serum sCD40L and IL-31 in the early phase of IgAN. Serum sCD40L may be a marker of the beginning of inflammation in IgAN.

DOI： 10.3390/jcm12052023

Association between Urinary Creatinine Excretion and Hypothyroidism in Patients with Chronic Kidney Disease. 査読国際誌

Natsumi Matsuoka-Uchiyama, Kenji Tsuji, Kensaku Takahashi, Kazuhiko Fukushima, Hidemi Takeuchi, Shinji Kitamura, Kenichi Inagaki, Haruhito A Uchida, Jun Wada

Diagnostics (Basel, Switzerland) 13 ( 4 ) 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

While hypothyroidism increases serum creatinine (Cr) levels, it is uncertain whether the elevation is mediated via a decline in the glomerular filtration rate (GFR) or the reflection of enhanced Cr production from the muscles or both. In the present study, we explored an association between urinary Cr excretion rate (CER) and hypothyroidism. A total of 553 patients with chronic kidney disease were enrolled in a cross-sectional study. Multiple linear regression analysis was performed to explore the association between hypothyroidism and urinary CER. The mean urinary CER was 1.01 ± 0.38 g/day and 121 patients (22%) had hypothyroidism. The multiple linear regression analysis revealed explanatory variables with urinary CER, including age, sex, body mass index, 24 h Cr clearance (24hrCcr), and albumin while hypothyroidism was not considered an independent explanatory variable. In addition, scatter plot analysis with regression fit line representing the association between estimated GFR calculated using s-Cr (eGFRcre) and 24hrCcr revealed that eGFRcre and 24hrCcr had strong correlations with each other in hypothyroid patients as well as euthyroid patients. Collectively, hypothyroidism was not considered an independent explanatory variable for urinary CER in the present study and eGFRcre is a useful marker to evaluate kidney function regardless of the presence of hypothyroidism.

DOI： 10.3390/diagnostics13040669

Suramin prevents the development of diabetic kidney disease by inhibiting NLRP3 inflammasome activation in KK-Ay mice. 査読

Kaori Oda, Satoshi Miyamoto, Ryo Kodera, Jun Wada, Kenichi Shikata

Journal of diabetes investigation 14 ( 2 ) 205 - 220 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS/INTRODUCTION: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-Ay /TaJcl (KK-Ay) mice against DKD progression. MATERIALS AND METHODS: Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. RESULTS: Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. CONCLUSIONS: These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD.

DOI： 10.1111/jdi.13930

Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank. 査読国際誌

Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Akihiro Katayama, Jun Wada, Miho Shimizu, Takashi Wada, Hiromasa Kitamura, Toshiaki Nakano, Hideki Yokoi, Motoko Yanagita, Shin Goto, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara

Journal of human genetics 68 ( 2 ) 55 - 64 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

DOI： 10.1038/s10038-022-01094-1

Metformin and Its Immune-Mediated Effects in Various Diseases. 査読国際誌

Ichiro Nojima, Jun Wada

International journal of molecular sciences 24 ( 1 ) 2023年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and CD+8 T cells. The activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) pathway may be involved in this process. Recent studies using Extracellular Flux Analyzer demonstrated that metformin alters the activities of glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and glutaminolysis, which tightly link to the modulation of cytokine production in CD4+ and CD+8 T cells in various disease states, such as virus infection, autoimmune diseases, aging and cancers.

DOI： 10.3390/ijms24010755

Editorial: Myriad types of cell death in nephropathy and their veiled potential. 査読国際誌

Jun Wada, Rashmi S Tupe, Isha Sharma

Frontiers in endocrinology 14 1251148 - 1251148 2023年

E3-ubiquitin ligases and recent progress in osteoimmunology. 査読国際誌

Yosuke Asano, Yoshinori Matsumoto, Jun Wada, Robert Rottapel

Frontiers in immunology 14 1120710 - 1120710 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies.

DOI： 10.3389/fimmu.2023.1120710

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia. 査読国際誌

Akinori Hara, Takashi Wada, Eri Muso, Shoichi Maruyama, Sawako Kato, Kengo Furuichi, Kenichi Yoshimura, Tadashi Toyama, Norihiko Sakai, Hiroyuki Suzuki, Tatsuo Tsukamoto, Mariko Miyazaki, Eiichi Sato, Masanori Abe, Yugo Shibagaki, Ichiei Narita, Shin Goto, Yuichi Sakamaki, Hitoshi Yokoyama, Noriko Mori, Satoshi Tanaka, Yukio Yuzawa, Midori Hasegawa, Takeshi Matsubara, Jun Wada, Katsuyuki Tanabe, Kosuke Masutani, Yasuhiro Abe, Kazuhiko Tsuruya, Shouichi Fujimoto, Shuji Iwatsubo, Akihiro Tsuda, Hitoshi Suzuki, Kenji Kasuno, Yoshio Terada, Takeshi Nakata, Noriaki Iino, Tadashi Sofue, Hitomi Miyata, Toshiaki Nakano, Takayasu Ohtake, Shuzo Kobayashi

Blood purification 52 ( 4 ) 373 - 381 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (β coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

DOI： 10.1159/000527900

A case of sitosterolaemia-caused systemic large-vessel stenosis mimicking Takayasu arteritis in which FDG-PET provided a clue for the differential diagnosis. 査読国際誌

Takato Nakadoi, Eri Katsuyama, Kazuya Matsumoto, Kenta Shidahara, Kei Hirose, Shoichi Nawachi, Yosuke Asano, Yu Katayama, Yoshia Miyawaki, Takayuki Katsuyama, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Hayato Tada, Jun Wada

Rheumatology advances in practice 7 ( 3 ) rkad096 2023年

Cover Image, Volume 24, Issue 12

Takashi Kadowaki, Hiroshi Maegawa, Hirotaka Watada, Daisuke Yabe, Koichi Node, Toyoaki Murohara, Jun Wada

Diabetes, Obesity and Metabolism 2022年12月

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetic Kidney Disease: A Multicenter, Open-Label, Prospective Study 査読

Haruhito A. Uchida, Hirofumi Nakajima, Masami Hashimoto, Akihiko Nakamura, Tomokazu Nunoue, Kazuharu Murakami, Takeshi Hosoya, Kiichi Komoto, Takashi Taguchi, Takaaki Akasaka, Kazuhito Shiosakai, Kotaro Sugimoto, Jun Wada

ADVANCES IN THERAPY 39 ( 11 ) 5158 - 5175 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Introduction Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment. Methods In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety. Results In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m(2). Conclusion Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction.

DOI： 10.1007/s12325-022-02294-z

Effects of Wnt-beta-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells 査読

Eisaku Morimoto, Kenichi Inagaki, Motoshi Komatsubara, Tomohiro Terasaka, Yoshihiko Itoh, Satoshi Fujisawa, Erika Sasaki, Yuki Nishiyama, Takayuki Hara, Jun Wada

JOURNAL OF THE ENDOCRINE SOCIETY 6 ( 10 ) 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ENDOCRINE SOC

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-beta-catenin signaling. However, the relation between Wnt-beta-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-beta-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

DOI： 10.1210/jendso/bvac121

A case of recurrent IgG4-related disease successfully treated with belimumab after remission of systemic lupus erythematosus 査読

Yu Katayama, Takayuki Katsuyama, Kenta Shidahara, Shoichi Nawachi, Yosuke Asano, Keiji Ohashi, Yoshia Miyawaki, Eri Katsuyama, Mariko Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Jun Wada

RHEUMATOLOGY 61 ( 10 ) E308 - E310 2022年10月

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