Calcium channel blocker in patients with chronic kidney disease

[Background] Chronic kidney disease (CKD) is involved in a progressive deterioration in renal function over the years and is now a global public health problem. Currently, reducing the number of patients progressing to end-stage renal failure is urgently necessary. Hypertension and CKD interact with each other, and good control of blood pressure (BP) can improve CKD patients’ prognosis. With the current global trend for more strict BP control, the importance of BP management and the need for medication to achieve this strict goal are increasing. Calcium channel blockers (CCBs), which target voltage-dependent calcium channels, are frequently used in combination with renin–angiotensin–aldosterone system inhibitors for CKD patients because of their strong BP-lowering properties and relatively few adverse side effects. Calcium channels have several subtypes, including L, N, T, P/Q, and R, and three types of CCBs, L-type CCBs, L-/T-type CCBs, and L-/N-type CCBs, that are available. Nowadays, the new functions and effects of the CCBs are being elucidated. [Conclusion] We should use different types of CCBs properly depending on their pharmacological effects, such as the strength of antihypertensive effects and the organ protection effects, taking into account the pathophysiology of the patients. In this article, the role and the use of CCBs in CKD patients are reviewed

Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition

Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury

<ORIGINAL ARTICLE>A Basic Study to Clarify the Porcelain-Metal Bonding Mechanism : Analysis of the Oxidized Surface of Gold Alloys by Reflection Electron Diffraction

陶材焼付用合金の合金表面を解析することは,その面が溶融した陶材と接するので,両者の界面反応と溶着機構を解明するために必要である。本研究は,卑金属成分として,lnとSnを総量1.5wt%含む金合金を, 1000℃で30sec-60min間,大気中で加熱し,酸化物など,表面状態の変化について,反射電子回折で解析した。 Snのみを添加した合金を除いて,それ以外の合金では,一様な酸化皮膜は形成されず合金そのものが部分的に露出している。生成した酸化物は,In_2O_3,とSnO_2で, In_20_3が広い組成範囲で優先的に形成される。 SnO_2は,Snが0.6wt%以下で,短時間の加熱では,回折リングが観察されないが,長時間の加熱になると観察されるようになる。酸化物の状態に対して加熱時間と卑金属成分濃度の依存性が認められる。高温酸化で生じた表面の凹凸は,加熱時間が増すに伴って増加する。これによって,陶材と合金の機械的結合の向上を期待できるが,合金そのものが露出していることの焼付機構への寄与は不明である。The oxide in contact with porcelain, the top layer of the oxidized surface of an alloy, is of critical importance when considering the reaction at the interface between porcelain and alloy. The present study uses Reflection High Energy Electron Diffraction to obtain detailed know-ledge of the oxidized surface of gold alloys containing small amounts of In and Sn (total 1.5 wt%), oxidized at 1000 ℃ in air for 30 sec to 60 min. The oxidized alloy surface is not always covered with a uniform oxide layer, in the case of alloys containing both In and Sn, or In alone, the alloy itself is partially exposed. The roughness of the oxidized surface due to high temperature oxidation increases with increasing oxidation times. In_2O_3, rather than Sn0_2, is preferentially formed when the Sn content is less than 0.6 wt% at short oxidation times, Sn0_2 can not be detected by the reflection electron diffraction

Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure

Pharmacological blockade of the N-and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Ca[v]2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Ca[v]2.2-/- mice with db/db (diabetic) mice on the C57BLKS background. Ca[v]2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Ca[v]2.2-/- mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Ca[v]2.2+/+ mice. Interestingly, diabetic heterozygous Ca[v]2.2+/- mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Ca[v]2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Ca[v]2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Ca[v]2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes

Importance of “meal first” strategy and effective situations of supplement use in elite athletes: Japan high performance sport center position stand

The “meal first” strategy is traditionally recommended for athletes' conditioning. However, the importance of the “meal first” principle has not been detailly well documented in athletes' lives. Supplement use has recently become a common part of athletes' diets, but unmonitored supplement use can cause negative consequences, such as anti-doping violations and health issues. Therefore, this review summarizes how the “meal first” strategy and planned supplement use are important for enhancing athletes’ health and performance. We believe that the “meal first” strategy is beneficial in terms of the following aspects: (1) consumption of multi-nutrients and other functional components simultaneously; (2) positive effects on psychological well-being; (3) contribution to athletes' health by way of mastication; and (4) less risk for anti-doping violations. Before supplement use, we recommend that athletes first verify their basic factors (e.g., diet, training, and sleep), given that the benefits of supplements are examined and demonstrated with the control of those factors. Otherwise, athletes cannot obtain maximal benefits from the supplements. In contrast, there are situations in which supplements in athletes' lives can be advantageous, such as (1) nutrient deficiency due to ongoing dietary characteristics; (2) interruption of meals due to disease; (3) inaccessibility of quality food during athletic travel; (4) difficulty preparing food due to societal restrictions associated with disasters or infection outbreaks; (5) having a meal before, during, or after exercise is difficult; and (6) achieving targeted intake of performance-enhancing ingredients is not practical. In summary, we emphasize that the “meal first” strategy is recommended for athletes' conditioning, but there are several contexts when supplement use can be more useful in athletes' lives

Long-term survival with RAS-associated autoimmune leukoproliferative disorder with somatic KRAS mutation:A case report

　RAS -associated autoimmune leukoproliferative disorder (RALD) is a recently reported rare nonmalignant autoimmune disorder. The characteristic clinical findings of RALD include monocytosis, leukocytosis, lymphoproliferation, and autoimmune phenomena. RALD is defined by somatic mutations in KRAS or NRAS . It is a new disease that was reported by Niemela and Takagi in 2011. The prognosis and incidence are currently unknown and the treatment strategy has not yet been established.　Here we describe the long-term survival of a patient with who displayed a somatic KRAS G12D mutation. His clinical features and labolatory data were overlapped with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Mercaptopurine hydrate, hydroxycarbamide and azacitizine were administered to control white blood cell count and improve clinical symptoms. He had a long survival time without hematopoietic stem cell transplantation

Increase of Total Nephron Albumin Filtration and Reabsorption in Diabetic Nephropathy

There is a hot debate concerning actual amount of albumin filtered through glomeruli and reabsorbed at proximal tubules in normal kidneys and diabetic conditions. To overcome current technical problems, we generated a drug-inducible megalin knockout mouse line, megalin(lox/lox);Ndrg1-CreER[T2] (or iMegKO), whose protein reabsorption can be shut off anytime by tamoxifen (Tam). After Tam administration, renal megalin protein expression was reduced by 92% compared to wild-type C57BL/6J mice, and renal reabsorption of intravenously-injected retinol binding protein was almost completely abrogated. Urinary albumin excretion increased to 175 μg/day (0.460 mg/mg-creatinine), suggesting that this was the amount of total nephron albumin filtration. Glomerular sieving coefficient of albumin was 1.7 x 10[-5]. By comparing streptozotocin-induced, Tam-treated, diabetic STZ;iMegKO mice with non-STZ;iMegKO mice, we estimated that daily albumin filtration was increased by 1.9-fold, reabsorption was increased by 1.8-fold, and reabsorption efficiency was reduced to 86% by development of diabetes (versus 96% in control). Such abnormalities were well normalized after insulin treatment. Another type 1 diabetic model of Akita;iMegKO mice showed equivalent results. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy, bringing new insights into our understanding of renal albumin dynamics in hyperfiltration status of diabetic nephropath

Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition

Guanylyl cyclase-A (GC-A) signaling, a natriuretic peptide receptor, exerts renoprotective effects by stimulating natriuresis and reducing blood pressure. Previously we demonstrated massive albuminuria with hypertension in uninephrectomized, aldosterone-infused, and high salt-fed (ALDO) systemic GC-A KO mice with enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in podocytes. In the present study, we examined the interaction between p38 MAPK and GC-A signaling. The administration of FR167653, p38 MAPK inhibitor, reduced systolic blood pressure (SBP), urinary albumin excretion, segmental sclerosis, podocyte injury, and apoptosis. To further investigate the local action of natriuretic peptide and p38 MAPK in podocytes, we generated podocyte-specific (pod) GC-A conditional KO (cKO) mice. ALDO pod GC-A cKO mice demonstrated increased urinary albumin excretion with marked mesangial expansion, podocyte injury and apoptosis, but without blood pressure elevation. FR167653 also suppressed urinary albumin excretion without reducing SBP. Finally, we revealed that atrial natriuretic peptide increased phosphorylation of MAPK phosphatase-1 (MKP-1) concomitant with inhibited phosphorylation of p38 MAPK in response to MAPK kinase 3 activation, thereby resulting in decreased mRNA expression of the apoptosis-related gene, Bax, and Bax/Bcl2 ratio in cultured podocytes. These results indicate that natriuretic peptide exerts a renoprotective effect via inhibiting phosphorylation of p38 MAPK in podocytes.</p

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

N型カルシウムチャネルの欠損による糖代謝の改善と血圧の低下を伴う糖尿病性腎症軽減作用に関する研究

京都大学0048新制・課程博士博士(医学)甲第20080号医博第4173号新制||医||1018(附属図書館)33196京都大学大学院医学研究科医学専攻(主査)教授 長船 健二, 教授 川口 義弥, 教授 小川 修学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA