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Search Results: 1 - 10 of 684 matches for " Kazuhiko Funabiki "
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Podocyte loss and albuminuria of KK-Ay mouse: A spontaneous animal model for human type 2 diabetic nephropathy  [PDF]
Yuji Ishikawa, Takamichi Ito, Mitsuo Tanimoto, Shinji Hagiwara, Masako Furukawa, Saori Yamaguchi, Keisuke Omote, Katsuhiko Asanuma, Tomohito Gohda, Yoshio Shimizu, Kazuhiko Funabiki, Satoshi Horikoshi, Yasuhiko Tomino
Journal of Diabetes Mellitus (JDM) , 2012, DOI: 10.4236/jdm.2012.23054
Abstract: Podocyte loss was well known in type 2 diabetic nephropathy patients. The objective of the present study was to determine the number of podocytes and the degree of albuminuria in diabetic KK-Ay/Ta (KK-Ay) mice which had been reported as diabetic nephropathy model. Diabetic KK-Ay mice, diabetic KK/Ta mice and non-diabetic BALB/cA Jcl (BALB/cA) mice were studied. We analyzed glomerular lesions in all mice by morphometric analysis and immunofluorescence to determine the number of podocytes. Level of urinary albumin was also measured. Glomerular enlargement and mesangial expansion were observed in KK-Ay mice. Mean number of podocytes per glomerulus (NG pod) in diabetic KK-Ay mice was significantly lower than that in non-diabetic BALB/cA mice. Mean NG pod/glomerular area (GA) per glomerulus was also significantly decreased in diabetic KK-Ay mice. The level of urinary albumin/creatinine ratio (ACR) in diabetic KK-Ay mice was significantly higher than that in non-diabetic BALB/cA mice. These data suggest that podocyte loss might induce albuminuria in KK-Ay mice. This finding confirmed our previous report that KK-Ay mice, especially in terms of histological findings, are a suitable animal model for glomerular injury in type 2 diabetic nephropathy.
Role of Mindin in Diabetic Nephropathy
Maki Murakoshi,Tomohito Gohda,Mitsuo Tanimoto,Kazuhiko Funabiki,Satoshi Horikoshi,Yasuhiko Tomino
Experimental Diabetes Research , 2011, DOI: 10.1155/2011/486305
Abstract: A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin-/F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy.
Role of Mindin in Diabetic Nephropathy
Maki Murakoshi,Tomohito Gohda,Mitsuo Tanimoto,Kazuhiko Funabiki,Satoshi Horikoshi,Yasuhiko Tomino
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/486305
Abstract: A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin-/F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy. 1. Introduction Diabetic nephropathy is a major cause of end-stage kidney disease (ESKD) in the United States, Japan, and most of Europe [1]. Although the etiology of this insidious disorder is not well understood, hyperglycemia and hypertension may play pivotal roles in the pathogenesis of diabetic nephropathy. Actually, almost 30% of diabetic patients develop diabetic nephropathy despite strict blood glucose and/or blood pressure control [2]. Chronic low-grade inflammation (so-called microinflammation) has been found to play roles in the pathogenesis of diabetes [3, 4] and has been identified as a risk factor for the development of diabetes [5, 6]. Moreover, diabetes has been proposed as a disease of the innate immune system [7]. In addition, the studies in recent years have shown that inflammation and inflammatory cytokines are determinants in the development of microvascular diabetic complications such as neuropathy, retinopathy, and nephropathy [8–11]. In 1991, Hasegawa et al. reported that glomerular basement membranes from diabetic rats induced significantly greater amounts of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) in cultured peritoneal macrophages than when these cells were incubated with basement membranes from nondiabetic rats [12]. Based on these findings, the authors suggested for the first time that inflammatory cytokines may participate in the pathogenesis of diabetic nephropathy [12]. At present, a number of clinical studies have suggested relationships between inflammatory cytokines and diabetic nephropathy [13, 14]. Inflammatory cytokines, that is, IL-1, interleukin-6 (IL-6), and interleukin-18 (IL-18) [15, 16], vascular endothelial growth factor (VEGF) [17, 18], monocyte chemoattractant protein-1 (MCP-1) [19, 20], and transforming growth factor-β (TGF-β)
Effect of the Direct Renin Inhibitor Aliskiren on Urinary Albumin Excretion in Spontaneous Type 2 Diabetic KK- Mouse
Masako Furukawa,Tomohito Gohda,Shinji Hagiwara,Mitsuo Tanimoto,Satoshi Horikoshi,Kazuhiko Funabiki,Yasuhiko Tomino
International Journal of Nephrology , 2013, DOI: 10.1155/2013/519130
Abstract: Objective. Although angiotensin II-mediated inflammation and extracellular matrix accumulation are considered to be associated with the progression of diabetic nephropathy, these processes have not yet been sufficiently clarified. The objective of this study was to determine whether the correction of the abnormal renal expression of MMPs and its inhibitors (MMPs/TIMPs) and cytokines following the administration of aliskiren to KK- mice results in a renoprotective effect. Methods. KK- mice were divided into two groups, that is, untreated (saline) and treated (aliskiren) groups. Systolic BP, HbA1c levels, and the albumin-creatinine ratio (ACR) were measured. The renal expression of MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (pro)renin receptor ((P)RR) was examined using real-time PCR and/or immunohistochemical staining. Renal MAPK and NF-κB activity were also examined by Western blot analyses and ELISA, respectively. Results. Significant decreases in systolic BP and ACR levels were observed in treated KK- mice compared with the findings in untreated KK- mice. Furthermore, increases in MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (P)RR expression, in addition to MAPK and NF-κB activity, were significantly attenuated by aliskiren administration. Conclusions. It appears that aliskiren improves albuminuria and renal fibrosis by regulating inflammation and the alteration of collagen synthesis and degradation. 1. Introduction Recent studies suggest that chronic inflammation and extracellular matrix (ECM) accumulation promote the progression of diabetic nephropathy (DN) [1, 2]. We have also reported the increased renal expression of monocyte chemotactic protein (MCP)-1, fibronectin, and type IV collagen in KK- mice [3–5], a frequently used animal model of type 2 diabetes (T2D) [6]. Furthermore, angiotensin (Ang) II induces the phosphorylation of mitogen-activated protein kinase (MAPK) and increases nuclear factor (NF)-κB binding activity in this mouse model [5]. Several studies have suggested that the renin-angiotensin system (RAS) is one of the major mediators of the progression of glomerular hypertension, inflammation, and tubulointerstitial fibrosis, which leads to the progression of DN [7–9]. Aliskiren is the first agent in a new class of orally effective direct renin inhibitors approved for hypertension treatment [10, 11]. In contrast to conventional RAS blockers, angiotensin-converting enzyme (ACE) inhibitors and Ang II type 1 receptor blockers (ARBs), aliskiren blocks RAS by directly inhibiting plasma renin activity and preventing the
Effect of Exercise on Kidney Function, Oxidative Stress, and Inflammation in Type 2 Diabetic KK-Ay Mice
Yuji Ishikawa,Tomohito Gohda,Mitsuo Tanimoto,Keisuke Omote,Masako Furukawa,Saori Yamaguchi,Maki Murakoshi,Shinji Hagiwara,Satoshi Horikoshi,Kazuhiko Funabiki,Yasuhiko Tomino
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/702948
Abstract: Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK- mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK- mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK- mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK- mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease.
Effect of Exercise on Kidney Function, Oxidative Stress, and Inflammation in Type 2 Diabetic KK-Ay Mice
Yuji Ishikawa,Tomohito Gohda,Mitsuo Tanimoto,Keisuke Omote,Masako Furukawa,Saori Yamaguchi,Maki Murakoshi,Shinji Hagiwara,Satoshi Horikoshi,Kazuhiko Funabiki,Yasuhiko Tomino
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/702948
Abstract: Exercise is recommended for the management of type 2 diabetes, but its effects on diabetic nephropathy (DN) are still unknown. We hypothesized that appropriate exercise improves early DN via attenuation of inflammation and oxidative damage. Type 2 diabetic KK- mice, a spontaneous DN model, underwent two different kinds of exercise (i.e., moderate and low intensity). Sedentary mice or those undergoing an exercise regimen causing no significant body weight loss were used. We examined the urinary excretion of albumin, number of podocytes and macrophages, renal expressions of HIF-1α and MCP-1, and biomarkers of oxidative stress such as urinary 8-OHdG and serum SOD. Exercise reduced urinary levels of albumin and also maintained the number of podocytes in the exercised KK- mice independently of improvements of overweight and hyperglycemia, although moderate-intensity exercise increased expression of HIF-1α. Sedentary KK- mice showed increased expression of MCP-1 and infiltration of macrophage, increased urinary 8-OhdG, and decreased serum SOD levels compared with exercised KK- mice. On the whole, low-intensity exercise attenuates progression of early DN without affecting marked renal ischemia. Reduction rates of urinary albumin and maintained podocyte numbers, with parallel improvements in oxidative damage and inflammation, are related to beneficial effects of exercise in diabetic kidney disease. 1. Introduction Recent studies suggest that a chronic inflammatory process and oxidative stress promote the progression of diabetic nephropathy (DN) [1–4]. We have also showed the presence of macrophage infiltration and increased MCP-1 expressions and levels in glomeruli and urine of KK- mice, a frequently used animal model of type 2 diabetes (T2D) [5, 6]. Furthermore, urinary 8-OHdG, a marker of oxidative DNA damage, was also increased in this mouse model [7]. Lifestyle modification, especially appropriate exercise, is recommended for the management of T2D through improvements of metabolic risk factors such as blood pressure, blood glucose, plasma lipids, and oxidative stress markers. On the other hand, this also consumes considerable amounts of oxygen, leading to production of high levels of reactive oxygen species (ROS). There is also evidence that ROS and high glucose exposure contribute to podocyte apoptosis in experimental DN [8]. It is considered that exercise-induced proteinuria is usually not permanent but evanescent [9, 10]. Moreover it is little known that moderate exercise has adverse effect on the renal function [11–14]. Several studies reported that
A Refutation of the Diagonal Argument  [PDF]
Kazuhiko Kotani
Open Journal of Philosophy (OJPP) , 2016, DOI: 10.4236/ojpp.2016.63027
Abstract: The diagonal argument is a very famous proof, which has influenced many areas of mathematics. However, this paper shows that the diagonal argument cannot be applied to the sequence of potentially infinite number of potentially infinite binary fractions. First, the original form of Cantor’s diagonal argument is introduced. Second, it is demonstrated that any natural number is finite, by a simple mathematical induction. Third, the concept of potential infinity, created by Aristotle, is presented. Typically, the natural numbers are considered potentially infinite. However, although any natural number is finite, there is also no limit to how large a natural number can be. Fourth, the concept of the potentially infinite decimal is introduced. Fifth, it is easily proven that the diagonal argument cannot be applied to the sequence of all n-bit binary fractions in the interval [0,1). Finally, the diagonal argument is shown to be inapplicable to the sequence of the potentially infinite number of potentially infinite binary fractions, which contains all n-bit binary fractions in the interval [0,1) for any n.
Differential Calculus Based on the Double Contradiction  [PDF]
Kazuhiko Kotani
Open Journal of Philosophy (OJPP) , 2016, DOI: 10.4236/ojpp.2016.64039
Abstract: The derivative is a basic concept of differential calculus. However, if we calculate the derivative as change in distance over change in time, the result at any instant is 0/0, which seems meaningless. Hence, Newton and Leibniz used the limit to determine the derivative. Their method is valid in practice, but it is not easy to intuitively accept. Thus, this article describes the novel method of differential calculus based on the double contradiction, which is easier to accept intuitively. Next, the geometrical meaning of the double contradiction is considered as follows. A tangent at a point on a convex curve is iterated. Then, the slope of the tangent at the point is sandwiched by two kinds of lines. The first kind of line crosses the curve at the original point and a point to the right of it. The second kind of line crosses the curve at the original point and a point to the left of it. Then, the double contradiction can be applied, and the slope of the tangent is determined as a single value. Finally, the meaning of this method for the foundation of mathematics is considered. We reflect on Dehaene’s notion that the foundation of mathematics is based on the intuitions, which evolve independently. Hence, there may be gaps between intuitions. In fact, the Ancient Greeks identified inconsistency between arithmetic and geometry. However, Eudoxus developed the theory of proportion, which is equivalent to the Dedekind Cut. This allows the iteration of an irrational number by rational numbers as precisely as desired. Simultaneously, we can define the irrational number by the double contradiction, although its existence is not guaranteed. Further, an area of a curved figure is iterated and defined by rectilinear figures using the double contradiction.
What Is Number?  [PDF]
Kazuhiko Kotani
Open Journal of Philosophy (OJPP) , 2017, DOI: 10.4236/ojpp.2017.72008
Abstract: What is number? This question is difficult to answer. Because the number is one of the most basic concepts, it is difficult to define the natural number with other concepts. Still, this problem is worth trying to answer. Now, everything is digitized and processed on computer. The importance of the number is increasing day by day. Now is time to consider what number is. Throughout the history of humankind, the ancient Greeks considered this question most profoundly. In particular, Plato defined the natural number one. The natural number one is equal, invariable and indivisible. These properties are intuitively acceptable. However, we have never seen or touched the natural number one itself. How can we know it? Socrates said that we know it before birth. This claim is called anamnesis. In this paper, we use a method, in which Socrates’ anamnesis is studied by the contemporary science. From a modern viewpoint, we could take Socrates’ anamnesis to mean that the natural number one is written in our genes. This article considers whether there is a biological entity corresponding to the natural number one. As a result, we find that a life itself is the prototype of the natural number one, and then properties of life make a critical base of DNA similar to the natural number one through natural selection. A life is an integrated and indivisible system, which resists the law of entropy. Furthermore, the basic properties of life enable natural selection, which conserves genetic information despite the law of entropy. The source of the power, which enables life to resist the law of entropy, is the genetic information. In conclusion, a life is a prototype of the natural number one. Furthermore, a life recognizes nature using natural numbers and resists the law of entropy using natural numbers.
Comparison of the Sampling Efficiency in Spatial Autoregressive Model  [PDF]
Yoshihiro Ohtsuka, Kazuhiko Kakamu
Open Journal of Statistics (OJS) , 2015, DOI: 10.4236/ojs.2015.51002
Abstract: A random walk Metropolis-Hastings algorithm has been widely used in sampling the parameter of spatial interaction in spatial autoregressive model from a Bayesian point of view. In addition, as an alternative approach, the griddy Gibbs sampler is proposed by [1] and utilized by [2]. This paper proposes an acceptance-rejection Metropolis-Hastings algorithm as a third approach, and compares these three algorithms through Monte Carlo experiments. The experimental results show that the griddy Gibbs sampler is the most efficient algorithm among the algorithms whether the number of observations is small or not in terms of the computation time and the inefficiency factors. Moreover, it seems to work well when the size of grid is 100.
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