Jun Nakazawa

Shiga University of Medical Science, Ōtu, Shiga Prefecture, Japan

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Publications (15)34.31 Total impact

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    ABSTRACT: Autophagy is an intracellular degradation system activated, across species, by starvation. Although accumulating evidence has shown that mammalian autophagy is involved in pathogenesis of several modern diseases, its physiological role to combat starvation has not been fully clarified. In this study, we analysed starvation-induced gluconeogenesis and ketogenesis in mouse strains lacking autophagy in liver, skeletal muscle or kidney. Autophagy-deficiency in any tissue had no effect on gluconeogenesis during starvation. Though skeletal muscle- and kidney-specific autophagy-deficiency did not alter starvation-induced increases in blood ketone levels, liver-specific autophagy-deficiency significantly attenuated this effect. Interestingly, renal as well as hepatic expression of HMG-CoA synthase 2 increased with prolonged starvation. Furthermore, during starvation, mice lacking autophagy both in liver and kidney showed even lower blood ketone levels and physical activity than mice lacking autophagy only in liver. Starvation induced massive lipid droplet formation in extra-adipose tissues including liver and kidney, which was essential for ketogenesis. Moreover, this process was impaired in the autophagy-deficient liver and kidney. These findings demonstrate that hepatic and renal autophagy are essential for starvation-induced lipid droplet formation and subsequent ketogenesis and, ultimately, for maintaining systemic energy homeostasis. Our findings provide novel biological insights into adaptive mechanisms to combat starvation in mammals.
    Full-text · Article · Jan 2016 · Scientific Reports
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    ABSTRACT: Background and objectives: We investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes. Design, setting, participants, & measurements: A total of 623 Japanese type 2 diabetic patients with eGFR≥60 ml/min per 1.73 m(2) were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR<30 ml/min per 1.73 m(2)), and the annual decline rate in eGFR. Results: During the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33-2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (>2.90 g/d) compared with the lowest quartile (<1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (-1.3 ml/min per 1.73 m(2)/y; 95% CI, -1.5 to -1.0) was significantly slower than those in the first quartile (-2.2; 95% CI, -2.4 to -1.8). Conclusions: Higher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial.
    No preview · Article · Nov 2015 · Clinical Journal of the American Society of Nephrology
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    ABSTRACT: Free fatty acid-bound albumin (FFA-albumin)-related oxidative stress is involved in the pathogenesis of proximal tubular cell (PTC) damage and subsequent renal dysfunction in patients with refractory proteinuria. Nicotinamide adenine dinucleotide (NAD) metabolism has recently been focused on as a novel therapeutic target for several modern diseases, including diabetes. This study was designed to identify a novel molecule in NAD metabolism to protect PTCs from lipotoxicity-related oxidative stress. Among 19 candidate enzymes involved in mammalian NAD metabolism, the mRNA expression level of nicotinamide n-methyltransferase (NNMT) was significantly increased in both the kidneys of FFA-albumin-overloaded mice and cultured PTCs stimulated with palmitate-albumin. Knockdown of NNMT exacerbated palmitate-albumin-induced cell death in cultured PTCs, whereas overexpression of NNMT inhibited it. Intracellular concentration of 1-Methylnicotinamide (1-MNA), a metabolite of NNMT, increased and decreased in cultured NNMT-overexpressing and -knockdown PTCs, respectively. Treatment with 1-MNA inhibited palmitate-albumin-induced mitochondrial reactive oxygen species generation and cell death in cultured PTCs. Furthermore, oral administration of 1-MNA ameliorated oxidative stress, apoptosis, necrosis, inflammation, and fibrosis in the kidneys of FFA-albumin-overloaded mice. In conclusion, NNMT-derived 1-MNA can reduce lipotoxicity-mediated oxidative stress and cell damage in PTCs. Supplementation of 1-MNA may have potential as a new therapy in patients with refractory proteinuria.
    Full-text · Article · Oct 2015 · Free Radical Biology and Medicine
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    ABSTRACT: Overcoming refractory massive proteinuria remains a clinical and research issue in diabetic nephropathy. This study was designed to investigate the pathogenesis of massive proteinuria in diabetic nephropathy, with a special focus on podocyte autophagy, a system of intracellular degradation that maintains cell and organelle homeostasis, using human tissue samples and animal models. Insufficient podocyte autophagy was observed histologically in diabetic patients and rats with massive proteinuria accompanied by podocyte loss, but not in those with no or minimal proteinuria. Podocyte-specific autophagy-deficient mice developed podocyte loss and massive proteinuria in a high-fat diet (HFD)-induced diabetic model for inducing minimal proteinuria. Interestingly, huge damaged lysosomes were found in the podocytes of diabetic rats with massive proteinuria and HFD-fed podocyte-specific autophagy-deficient mice. Furthermore, stimulation of cultured podocytes with sera from diabetic patients and rats with massive proteinuria impaired autophagy, resulting in lysosome dysfunction and apoptosis. These results suggest that autophagy plays a pivotal role in maintaining lysosome homeostasis in podocytes under diabetic conditions, and that its impairment is involved in the pathogenesis of podocyte loss leading to massive proteinuria in diabetic nephropathy. These results may contribute to the development of new therapeutic strategy for advanced diabetic nephropathy.
    No preview · Article · Sep 2015 · Diabetes
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    ABSTRACT: We report a case involving a 43-year-old Japanese woman with steroid-resistant focal segmental glomerular sclerosis (FSGS) and severe renal dysfunction, which was ameliorated by low-density lipoprotein apheresis (LDL-A). She had been treated with steroid therapy, but had experienced anuria for over 10 weeks and required hemodialysis. She was then treated with LDL-A, which resulted in improved urinary protein excretion and renal function. Her renal function recovered after 97 days of hemodialysis therapy. This case suggests that LDL-A may represent an effective rescue treatment in patients with FSGS and long-term anuria.
    Full-text · Article · Sep 2015 · Internal Medicine
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    ABSTRACT: Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with higher energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARɑ-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Biochemical and Biophysical Research Communications
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    ABSTRACT: A 74-year-old man with diabetes mellitus, hypertension and dyslipidemia was referred to our department due to the deterioration of renal function, proteinuria and hematuria. From his symptoms and laboratory findings, we suspected systemic lupus erythematosus (SLE) and planned an additional examination. However, he was admitted to our hospital due to fever and acute renal failure with severe hyperkalemia before the next consultation day. Acute exacerbation of lupus nephritis was suspected. We started oral prednisolone with continuous hemodialysis for the treatment of the hyperkalemia. Since his symptoms and examinations fulfilled the diagnostic criteria of SLE, he was diagnosed with late-onset SLE and lupus nephritis. Although his condition improved after the treatment with prednisolone, pancytopenia and hypocomplementemia were not improved. We then added mizoribine to the prednisolone. However, the pancytopenia and hypocomplementemia continued. We therefore initiated immunoadsorption plasmapheresis (IAPP). After this IAPP treatment, his symptoms and laboratory findings improved without recurrence. This case indicates that IAPP is one of the effective options for the treatment of lupus nephritis, especially in elderly patients, to lower the risk of immunosuppressant-related adverse events.
    No preview · Article · Jan 2015 · Nihon Toseki Igakkai Zasshi
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    ABSTRACT: Diabetic ketoacidosis is one of the most serious acute complications of diabetes mellitus. Arterial thrombosis complicating diabetic ketoacidosis (DKA) is a relatively common concomitant life-threatening illness. However, acute abdominal aortic thrombosis in DKA is very rare. We report a case of a 65-year-old woman who presented with abdominal aortic thrombus complicating DKA. She was brought to our hospital because of loss of consciousness. Her initial laboratory examination showed that glucose was 407 mg/dl, ketone bodies were positive, and pH was 6.91. Thus, we diagnosed her as having diabetic ketoacidosis. However, physical examination revealed pulseless femoral arteries, and laboratory testing revealed elevated lactate, D-dimer, and serum potassium levels. She complained of abdominal pain and had a bloody stool after admission. Initial non-contrast computed tomography (CT) did not show the occlusion of the arteries. Eighteen hours after admission, we found severe cyanosis of her bilateral lower limbs, and the contrast-enhanced CT revealed the thrombus in abdominal aorta extending into the bilateral common iliac arteries. This case indicates that DKA can be complicated by thrombosis. We should maintain a high index of suspicion for thrombosis in patients with DKA.
    No preview · Article · Sep 2013 · Diabetology International
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    ABSTRACT: A 62-year-old man with a 20-year history of non-insulin-dependent diabetes mellitus was admitted to our hospital because of the rapid deterioration of his renal function and increased proteinuria. He had swelling of parotid glands and interstitial pneumonia detected by chest X-ray and computed tomography. He had hypergammaglobulinemia and hypocomplementemia. Urinary β2-MG and NAG were elevated. A renal biopsy revealed tubulointerstitial nephritis and IgG4-positive plasma cell infiltration into the tubulointerstitium in addition to the enlargement of the glomeruli expansion of and the mesangial matrix. He was therefore diagnosed as having IgG4-related kidney disease complicated with diabetic nephropathy. Prednisolone therapy improved his renal function and urinary protein. The dosage of insulin was initially 26 units per day and was increased to 92 units per day to maintain the optimal glucose levels after the treatment. This is the first case of IgG4-related kidney disease superimposed on diabetic nephropathy. This case emphasizes the importance of early diagnosis of other kidney diseases by renal biopsy when we encounter the case of diabetic nephropathy with rapid deterioration of renal function to avoid the induction of dialysis therapy.
    No preview · Article · Sep 2012 · Journal of the Japan Diabetes Society
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    ABSTRACT: Diabetic patients are at higher risk of failure to recover after acute kidney injury, however, the mechanism and therapeutic strategies remain unclear. Erythropoietin is cytoprotective in a variety of non-haematopoietic cells. The aim of the present study was to clarify the mechanism of diabetes-related acceleration of renal damage after ischaemia-reperfusion injury and to examine the therapeutic potential of asialoerythropoietin, a non-haematopoietic erythropoietin derivative, against ischaemia-reperfusion-induced acute kidney injury in diabetic mice. C57BL/6J mice with and without streptozotocin-induced diabetes were subjected to 30 min unilateral renal ischaemia-reperfusion injury at 1 week after induction of diabetes. They were divided into four group: (i) non-diabetic plus ischaemia-reperfusion injury; (ii) non-diabetic plus ischaemia-reperfusion injury plus asialoerythropoietin (3000 IU/kg bodyweight); (iii) diabetic plus ischaemia-reperfusion injury; and (iv) diabetic plus ischemia-reperfusion injury plus asialoerythropoietin. Experiments were conducted at the indicated time periods after ischaemia-reperfusion injury. Ischaemia-reperfusion injury of diabetic kidney resulted in significantly low protein expression levels of bcl-2, an anti-apoptotic molecule, and bone morphogenetic protein-7 (BMP-7), an anti-fibrotic and pro-regenerative factor, compared with non-diabetic kidneys. Diabetic kidney subsequently showed severe damage including increased tubular cell apoptosis, tubulointerstitial fibrosis and decreased tubular proliferation, compared with non-diabetic kidney. Treatment with asialoerythropoietin induced bcl-2 and BMP-7 expression in diabetic kidney and decreased tubular cell apoptosis, tubulointerstitial fibrosis and accelerated tubular proliferation. Reduced induction bcl-2 and BMP-7 may play a role in the acceleration of renal damage after ischaemia-reperfusion injury in diabetic kidney. The renoprotective effects of asialoerythropoietin on acute kidney injury may be mediated through the induction of bcl-2 and BMP-7.
    Full-text · Article · Feb 2010 · Nephrology

  • No preview · Article · Jan 2008 · Nihon Toseki Igakkai Zasshi
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    ABSTRACT:   We examined whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) can affect the anemia and iron status of hemodialysis patients. We recruited patients from six dialysis centers who had undergone maintenance hemodialysis for at least four months. We examined the use of NSAIDs during the past three months based on their medical records and assigned the patients to three groups (group A, non-NSAID group; group B, aspirin group; and group C, non-aspirin NSAID group). Of the 446 patients, 95 (21.3%) were treated with aspirin and 103 (23.1%) were treated with non-aspirin NSAIDs. The serum iron level and transferrin saturation (TSAT) were significantly lower in group C patients than those in group A. However, the ratio of the patients who were administrated iron preparations during the past three months was significantly higher than that in the other two groups. The incidences of positive fecal occult blood tests did not differ substantially between the three groups. The ratios of the patients who were administrated recombinant human erythropoietin were the same between three groups. Using a multiple regression analysis, the administration of non-aspirin NSAIDs was identified as an independent factor for the decreased serum iron and the decreased TSAT levels. A multiple logistic regression analysis revealed that the patients using non-aspirin NSAIDs had an increased the requirement for iron preparation therapy (OR 2.03, 95% CI, 1.28-3.22). The use of non-aspirin NSAIDs may therefore increase the risk of the iron deficiency in patients undergoing hemodialysis.
    No preview · Article · May 2007 · Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
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    ABSTRACT: A middle-aged woman with rheumatoid arthritis was admitted because of cellulitis on the leg. Twenty-four hours after admission haemorrhagic blisters and bullae appeared on the lower extremity. Despite intensive therapy she died due to multiple organ failure at 50 h after admission. Post-mortem examination revealed diffuse necrosis of fascia in her leg. Bacteriological study showed Escherichia coli in her blood cultures and fluid from a bulla, indicating that she had necrotizing fasciitis resulting from Escherichia coli. Necrotizing fasciitis is an uncommon but potentially fatal infection; thus, this disease should be considered in the differential diagnosis of any cutaneous manifestations in patients with rheumatoid arthritis.
    No preview · Article · Mar 2007
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    ABSTRACT: We have encountered a 68-year-old Japanese woman with limited cutaneous systemic sclerosis who developed de novo onset of accelerated hypertension and renal dysfunction; thus we diagnosed scleroderma renal crisis. Anticentromere antibody alone was identified, and not anti-DNA topoisomerase I antibody, anti-RNA polymerase antibodies, anti-Th/To antibodies, or antiribonucleoprotein antibodies, even with use of immunoprecipitation assay. She was successfully treated with angiotensin-converting enzyme inhibitor. This case, scleroderma renal crisis with detection of anticentromere antibody, is thought to be extremely uncommon.
    No preview · Article · Feb 2006 · Modern Rheumatology
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    ABSTRACT: A previously healthy 19-year-old girl was admitted to our hospital because of hyperkalemia. Pseudohyperkalemia was diagnosed because there was a marked difference between levels of serum and plasma potassium. Her plasma potassium level was markedly increased after 6-hour in vitro incubation of blood at room temperature, suggesting excessive potassium release from red blood cells without coagulation. The plasma potassium levels of the patient and her father were markedly elevated in blood specimens incubated in vitro at 4 degrees C, but not at 37 degrees C. These data indicated pseudohyperkalemia syndrome caused by abnormal leakage of potassium from red blood cells at the lower temperatures.
    No preview · Article · Sep 2005 · Internal Medicine