Publications by authors named "Osamu Yamazaki"

58 Publications

Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism.

Hypertens Res 2021 Jul 29. Epub 2021 Jul 29.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Pendrin is a Cl/HCO exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.
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http://dx.doi.org/10.1038/s41440-021-00710-5DOI Listing
July 2021

Renal Involvement as Rare Acute Tubulointerstitial Nephritis in a Patient with Eosinophilic Disorder Treated with Early Add-on Administration of Mepolizumab.

Intern Med 2021 Jun 5. Epub 2021 Jun 5.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 39-year-old man presented with peripheral eosinophilia, pulmonary eosinophilic infiltrate, and renal failure due to acute tubulointerstitial nephritis (TIN). He had experienced childhood asthma and was negative for anti-neutrophil cytoplasmic antibody (ANCA). He was tentatively diagnosed with ANCA-negative eosinophilic granulomatous polyangiitis (EGPA) or idiopathic hypereosinophilic syndrome (HES). Renal involvement of isolated TIN with eosinophil infiltration is rare in EGPA and HES and does not seem to have a good prognosis in the literature. However, his condition improved well with corticosteroids and mepolizumab. The revised classification of EGPA based on the etiology should dictate the proper treatment in suspected EGPA patients with nonsystemic vasculitis.
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http://dx.doi.org/10.2169/internalmedicine.7490-21DOI Listing
June 2021

Body mass index and risk of recurrent falls in community-dwelling Japanese aged 40-74 years: The Murakami cohort study.

Geriatr Gerontol Int 2021 Jun 21;21(6):498-505. Epub 2021 Apr 21.

Department of Orthopaedic Surgery, Niigata University Medical and Dental Hospital, Niigata, Japan.

Aims: A prior meta-analysis found that obesity (body mass index [BMI] ≥ 30 kg/m ) was associated with a high fall risk, while being overweight (BMI≥25, <30 kg/m ) was associated with the lowest fall risk. However, whether these associations hold true for East Asians is unknown. This study aimed to assess the association between BMI and incidence of recurrent falls in Japanese aged 40-74 years.

Methods: This 5-year follow-up cohort study involved 7538 community-dwelling individuals who did not experience recurrent falls in the year before the baseline study. Information on demographics, body size, lifestyle, and disease history was obtained using a self-administered questionnaire. BMI was categorized as <18.5 (underweight), 18.5-20.6 (low-normal), 20.7-22.7 (mid-normal, reference), 22.8-24.9 (high-normal), and ≥ 25.0 kg/m (overweight). The outcome was recurrent falls reported, and fall history in the previous year was recorded as none, once, or twice or more (recurrent falls).

Results: Mean BMI was 23.5 kg/m (SD 2.9) for men and 22.7 kg/m (SD 3.2) for women. The adjusted odds ratio (OR) for recurrent falls in the BMI ≥25 group was significantly higher (1.41, 95%CI: 1.02-1.93) than that in the reference group. The adjusted OR in the BMI ≥25 group was significantly higher than that in the reference group for the age ≥ 60 subgroup (1.62, 95%CI: 1.09-2.40), but not for the age < 60 subgroup (OR = 1.04, 95%CI: 0.60-1.80).

Conclusions: Being overweight may be a risk factor for recurrent falls in community-dwelling older Japanese. Further studies are needed to determine the underlying mechanism. Geriatr Gerontol Int 2021; 21: 498-505.
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http://dx.doi.org/10.1111/ggi.14167DOI Listing
June 2021

A Ruptured Jejunal Arterial Aneurysm in a Young Woman Undergoing Chronic Hemodialysis Due to Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Intern Med 2021 Mar 29. Epub 2021 Mar 29.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 21-year-old woman was admitted to our hospital because of massive intestinal bleeding. She started hemodialysis due to myeloperoxidase antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at 18 years of age. Her ANCA titers remained stable; however, her C-reactive protein increased on 5 mg/day prednisolone before admission. Computed tomography angiography revealed a ruptured jejunal arterial aneurysm. Transcatheter arterial embolization, blood transfusion and the reinforcement of steroid therapy resolved her symptoms of AAV. Our case of a young patient with AAV and medium-sized arterial vasculitis is rare and emphasizes that the ANCA titer does not always rise, especially in patients with nonrenal vasculitis flare-ups.
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http://dx.doi.org/10.2169/internalmedicine.6721-20DOI Listing
March 2021

Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model.

Commun Biol 2020 10 15;3(1):575. Epub 2020 Oct 15.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 173-8605, Japan.

Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.
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http://dx.doi.org/10.1038/s42003-020-01298-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562875PMC
October 2020

Pyuria without Casts and Bilateral Kidney Enlargement Are Probable Hallmarks of Severe Acute Kidney Injury Induced by Acute Pyelonephritis: A Case Report and Literature Review.

Intern Med 2021 Jan 5;60(2):293-298. Epub 2020 Sep 5.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

The patient was a 38-year-old man who had experienced nausea and fever for a few days and presented with back pain, oliguria, and pyuria, suggesting acute pyelonephritis (APN). He showed acute kidney injury (AKI) with bilateral kidney enlargement and was using nonsteroidal anti-inflammatory drugs (NSAIDs). AKI-induced by APN was confirmed by kidney biopsy. The AKI was successfully treated with antibiotic therapy. A search of the relevant literature for reports on histopathologically-proven APN-induced severe AKI revealed that the key characteristics were bilateral kidney enlargement with pyuria without casts. Oligoanuria was frequently associated with APN-induced severe AKI, and NSAID use may be a possible risk factor. Prompt antibiotic treatment based on the clinical characteristics of APN-induced AKI can improve the renal outcome.
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http://dx.doi.org/10.2169/internalmedicine.5721-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872795PMC
January 2021

Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review.

Int J Mol Sci 2020 Jul 28;21(15). Epub 2020 Jul 28.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo 173-8605, Japan.

The kidney and the vasculature play crucial roles in regulating blood pressure. The ubiquitin proteasome system (UPS), a multienzyme process mediating covalent conjugation of the 76-amino acid polypeptide ubiquitin to a substrate protein followed by proteasomal degradation, is involved in multiple cellular processes by regulating protein turnover in various tissues. Increasing evidence demonstrates the roles of UPS in blood pressure regulation. In the kidney, filtered sodium is reabsorbed through diverse sodium transporters and channels along renal tubules, and studies conducted till date have provided insights into the complex molecular network through which ubiquitin ligases modulate sodium transport in different segments. Components of these pathways include ubiquitin ligase neuronal precursor cell-expressed developmentally downregulated 4-2, Cullin-3, and Kelch-like 3. Moreover, accumulating data indicate the roles of UPS in blood vessels, where it modulates nitric oxide bioavailability and vasoconstriction. Cullin-3 not only regulates renal salt reabsorption but also controls vascular tone using different adaptor proteins that target distinct substrates in vascular smooth muscle cells. In endothelial cells, UPS can also contribute to blood pressure regulation by modulating endothelial nitric oxide synthase. In this review, we summarize current knowledge regarding the role of UPS in blood pressure regulation, focusing on renal sodium reabsorption and vascular function.
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http://dx.doi.org/10.3390/ijms21155358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432568PMC
July 2020

Dietary calcium and vitamin K are associated with osteoporotic fracture risk in middle-aged and elderly Japanese women, but not men: the Murakami Cohort Study.

Br J Nutr 2021 02 7;125(3):319-328. Epub 2020 May 7.

Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Although dietary Ca, vitamin D and vitamin K are nutritional factors associated with osteoporosis, little is known about their effects on incident osteoporotic fractures in East Asian populations. This study aimed to determine whether intakes of these nutrients predict incident osteoporotic fractures. We adopted a cohort study design with a 5-year follow-up. Subjects were 12 794 community-dwelling individuals (6301 men and 6493 women) aged 40-74 years. Dietary intakes of Ca, vitamin D and vitamin K were assessed with a validated FFQ. Covariates were demographic and lifestyle factors. All incident cases of major osteoporotic limb fractures, including those of the distal forearm, neck of humerus, neck or trochanter of femur and lumbar or thoracic spine were collected. Hazard ratios (HR) for energy-adjusted Ca, vitamin D and vitamin K were calculated with the residual method. Mean age was 58·8 (sd 9·3) years. Lower energy-adjusted intakes of Ca and vitamin K in women were associated with higher adjusted HR of total fractures (Pfor trend = 0·005 and 0·08, respectively). When vertebral fracture was the outcome, Pfor trend values for Ca and vitamin K were 0·03 and 0·006, respectively, and HR of the lowest and highest (reference) intake groups were 2·03 (95 % CI 1·08, 3·82) and 2·26 (95 % CI 1·19, 4·26), respectively. In men, there were null associations between incident fractures and each of the three nutrient intakes. Lower intakes of dietary Ca and vitamin K were independent lifestyle-related risk factors for osteoporotic fracture in women but not men. These associations were robust for vertebral fractures, but not for limb fractures.
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http://dx.doi.org/10.1017/S0007114520001567DOI Listing
February 2021

Upregulation of renal Na-K-2Cl cotransporter 2 in obese diabetes mellitus via a vasopressin receptor 2-dependent pathway.

Biochem Biophys Res Commun 2020 04 5;524(3):710-715. Epub 2020 Feb 5.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, 173-8605, Japan. Electronic address:

Na-K-2Cl cotransporter 2 (NKCC2) in thick ascending limb (TAL) in the kidney plays a central role in tubuloglomerular feedback (TGF) system by sensing NaCl delivery to the distal tubules. Although accumulating data indicate that dysregulated TGF contributes to the progression of diabetic complications, the regulation of NKCC2 in diabetes mellitus (DM) remains unclear. We here show that NKCC2 is overactivated via a vasopressin receptor 2 (V2R)-dependent mechanism in db/db mice, a mouse model of obese DM. Compared with db/+ mice, we found that both aquaporin 2 and NKCC2 levels were significantly increased in the kidney in db/db mice. Immunohistochemical analysis of V2R and NKCC2 in the kidney demonstrated that V2R is present in the TAL, as well as in the collecting duct. Moreover, the administration of tolvaptan, a selective V2R antagonist, sharply decreased aquaporin 2 and NKCC2 in db/db mice, confirming the causal role of V2R signaling in NKCC2 induction in this model. Although tolvaptan reduced aquaporin 2 abundance also in db/+ mice, its effect on NKCC2 was modest compared with db/db mice. In total kidney lysates, uromodulin expression was not altered between db/+ and db/db mice, suggesting that V2R signaling alters NKCC2 without altering uromodulin levels. These data implicate the dysregulation of NKCC2 in the pathophysiology of type 2 DM, and underscore the complex nature of fluid volume disorders in diabetic kidney disease.
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http://dx.doi.org/10.1016/j.bbrc.2020.01.142DOI Listing
April 2020

Total physical activity and risk of chronic low back and knee pain in middle-aged and elderly Japanese people: The Murakami cohort study.

Eur J Pain 2020 04 25;24(4):863-872. Epub 2020 Feb 25.

Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Background: Specific components of physical activity, such as vigorous exercise and heavy occupational work, are known to increase the risk of chronic low back pain (CLBP) and chronic knee pain (CKP), but impacts of other components are less known. This study aimed to assess the relationship between total physical activity and risk of CLBP and CKP from a public health perspective.

Methods: Participants were 7,565 individuals, aged 40-74 years, who did not have CLBP or CKP, and who participated in the 5-year follow-up survey. A self-administered questionnaire was used to obtain information on demographics, body size and lifestyle (including physical activity) in the baseline survey in 2011-2013, and on CLBP and CKP using Short Form 36 (SF-36) in the follow-up survey. Sitting, standing, walking and strenuous work for occupational activity were assessed for total physical activity, and walking slowly, walking quickly, light to moderate exercise and strenuous exercise were assessed for leisure-time physical activity using metabolic equivalent hours/day (METs score).

Results: Mean age of participants was 60.1 years (SD, 8.8). Participants with higher METs scores had a significantly higher risk of CKP (p for trend = 0.0089, OR of 4th quartile = 1.29, 95% CI: 1.04-1.59 vs. 1st quartile), but not CLBP. An intermediate leisure-time METs score was associated with a lower risk of CLBP (OR = 0.75, 95%CI: 0.61-0.92 vs. 0 METs-group).

Conclusions: A high level of total physical activity may increase the risk of CKP, whereas an intermediate level of leisure-time physical activity may decrease the risk of CLBP, in middle-aged and elderly individuals.

Significance: Evidence on the longitudinal association between total physical activity and CLBP and CKP in middle-aged and elderly people is lacking. We conducted a cohort study to assess this association, and found that high levels of total physical activity increased risk of CKP, and intermediate levels of leisure-time physical activity decreased risk of CLBP. This suggests that the effect of physical activity on chronic pain differed by pain site.
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http://dx.doi.org/10.1002/ejp.1535DOI Listing
April 2020

Modifiable factors associated with symptomatic knee osteoarthritis: The Murakami cohort study.

Maturitas 2019 Oct 25;128:53-59. Epub 2019 Jul 25.

Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. Electronic address:

Objectives: Modifiable risk factors for knee osteoarthritis (OA) have not been studied in detail. This study aimed to determine lifestyle-related modifiable factors of symptomatic knee osteoarthritis in an East Asian population.

Study Design: This 5-year cohort study involved 11,091 individuals (age range 40-72 years) living in the Murakami region of Niigata, Japan, who did not have a history of knee OA. At baseline, information on sociodemographic characteristics, body size, lifestyle, and living condition was obtained using a self-administered questionnaire.

Main Outcome Measures: Incident symptomatic knee OA observed at hospitals and orthopaedic clinics in the five years to 2016. Clinical grades of knee OA were based on the Kellgren-Lawrence scale. P for trend was assessed to examine linear associations between predictors and the outcome in multiple logistic regression analysis.

Results: The mean age of participants was 58.1 (SD 9.3) years. The number of cases of grade 2 or more incident knee OA was 429. In men, older age (P for trend < 0.0001), higher BMI (P for trend < 0.0001), higher METs score (P for trend = 0.0150), less smoking (P for trend = 0.0249), and lower green tea consumption (P for trend = 0.0437) were associated with incident knee OA. In women, older age (P for trend < 0.0001), higher BMI (P for trend < 0.0001), and alcohol consumption (P = 0.0153) were associated with incident knee OA.

Conclusions: Several lifestyle-related factors were found to be associated with incident knee OA and exhibited sex-dependent differences. In particular, higher consumption of green tea was associated with a lower incidence of knee OA in men.
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http://dx.doi.org/10.1016/j.maturitas.2019.06.013DOI Listing
October 2019

A Case of Rheumatoid Arthritis Presenting with Renal Thrombotic Microangiopathy Probably due to a Combination of Chronic Tacrolimus Arteriolopathy and Severe Hypertension.

Case Rep Nephrol 2019 6;2019:3923190. Epub 2019 Mar 6.

Department of Internal Medicine, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.

A 51-year-old woman with rheumatoid arthritis presented with mild hypertension 20 months after tacrolimus treatment and developing proteinuria 24 months after the treatment. Tacrolimus was discontinued 27 months after the treatment, followed by heavy proteinuria, accelerated hypertension, and deteriorating renal function without ocular fundus lesions as a clinical sign of malignant hypertension. Renal biopsy revealed malignant nephrosclerosis characterized by subacute and chronic thrombotic microangiopathy (TMA), involving small arteries, arterioles, and glomeruli. Focal segmental glomerulosclerosis, probably secondary to chronic TMA, was identified as a cause of heavy proteinuria. The zonal tubulointerstitial injury caused by subacute TMA may have mainly contributed to deteriorating renal function. The presence of nodular hyalinosis in arteriolar walls was indicative of tacrolimus-associated nephrotoxicity. Together with other antihypertensive drugs, administration of aliskiren stabilized renal function with reducing proteinuria. Owing to the preexisting proteinuria prior to severe hypertension and the complex renal histopathology, we postulated that chronic TMA, which was initially triggered by tacrolimus, was aggravated by severe hypertension, resulting in overt renal TMA.
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http://dx.doi.org/10.1155/2019/3923190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431373PMC
March 2019

A Patient with MPO-ANCA-positive IgA Nephropathy Diagnosed with the Clinical Onset of Macrohematuria.

Intern Med 2019 Jul 28;58(14):2051-2056. Epub 2019 Mar 28.

Department of Internal Medicine, Teikyo University School of Medicine, Japan.

A 21-year-old woman presented with renal dysfunction during macrohematuria. A kidney biopsy revealed IgA nephropathy with a small percentage of crescent formation and macrohematuria-associated tubular injury. Macrohematuria-associated acute kidney injury could explain her renal dysfunction. However, she was seropositive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) and showed fibrin deposition around one arteriole. Corticosteroids and mycophenolate mofetil were administered as for ANCA vasculitis, and the serum creatinine, abnormal urinalysis and MPO-ANCA titer all gradually ameliorated. The presence of extra-glomerular vasculitis, which was probably induced by ANCA, suggested that MPO-ANCA was an exacerbating factor for her prolonged renal dysfunction. This condition has so far only rarely been addressed in ANCA-positive IgA nephropathy.
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http://dx.doi.org/10.2169/internalmedicine.2475-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702016PMC
July 2019

Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model.

Sci Rep 2019 02 11;9(1):1732. Epub 2019 Feb 11.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Recent clinical studies indicate that the disturbed phosphate metabolism in chronic kidney disease (CKD) may facilitate kidney injury; nonetheless, the causal role of phosphate in CKD progression remains to be elucidated. Here, we show that intestinal phosphate binding by sucroferric oxyhydroxide (SF) ameliorates renal injury in the rat remnant kidney model. Sprague-Dawley rats received 5/6 nephrectomy (RK) and had a normal chow or the same diet containing SF (RK + SF). RK rats showed increased plasma FGF23 and phosphate levels, which were suppressed by SF administration. Of note, albuminuria in RK rats was significantly ameliorated by SF at both 4 and 8 weeks. SF also attenuated glomerulosclerosis and tubulointerstitial injury. Moreover, several different approaches confirmed the protective effects on podocytes, explaining the attenuation of glomerulosclerosis and albuminuria observed in this study. As a possible mechanism, we found that SF attenuated renal inflammation and fibrosis in RK rats. Interestingly, von Kossa staining of the kidney revealed calcium phosphate deposition in neither RK nor RK + SF rats; however, plasma levels of calciprotein particles were significantly reduced by SF. These data indicate that latent positive phosphate balance accelerates CKD progression from early stages, even when overt ectopic calcification is absent.
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http://dx.doi.org/10.1038/s41598-018-38389-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370755PMC
February 2019

Calcineurin dephosphorylates Kelch-like 3, reversing phosphorylation by angiotensin II and regulating renal electrolyte handling.

Proc Natl Acad Sci U S A 2019 02 4;116(8):3155-3160. Epub 2019 Feb 4.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 173-8605 Tokyo, Japan;

Calcineurin is a calcium/calmodulin-regulated phosphatase known for its role in activation of T cells following engagement of the T cell receptor. Calcineurin inhibitors (CNIs) are widely used as immunosuppressive agents; common adverse effects of CNIs are hypertension and hyperkalemia. While previous studies have implicated activation of the Na-Cl cotransporter (NCC) in the renal distal convoluted tubule (DCT) in this toxicity, the molecular mechanism of this effect is unknown. The renal effects of CNIs mimic the hypertension and hyperkalemia that result from germ-line mutations in with-no-lysine (WNK) kinases and the Kelch-like 3 (KLHL3)-CUL3 ubiquitin ligase complex. WNK4 is an activator of NCC and is degraded by binding to KLHL3 followed by WNK4's ubiquitylation and proteasomal degradation. This binding is prevented by phosphorylation of KLHL3 at serine 433 (KLHL3) via protein kinase C, resulting in increased WNK4 levels and increased NCC activity. Mechanisms mediating KLHL3 dephosphorylation have heretofore been unknown. We now demonstrate that calcineurin expressed in DCT is a potent KLHL3 phosphatase. In mammalian cells, the calcium ionophore ionomycin, a calcineurin activator, reduces KLHL3 levels, and this effect is reversed by the calcineurin inhibitor tacrolimus and by siRNA-mediated knockdown of calcineurin. In vivo, tacrolimus increases levels of KLHL3, resulting in increased levels of WNK4, phosphorylated SPAK, and NCC. Moreover, tacrolimus attenuates KLHL3-mediated WNK4 ubiquitylation and degradation, while this effect is absent in KLHL3 with S433A substitution. Additionally, increased extracellular K induced calcineurin-dependent dephosphorylation of KLHL3 These findings demonstrate that KLHL3 is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.
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http://dx.doi.org/10.1073/pnas.1817281116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386661PMC
February 2019

Electrolyte transport in the renal collecting duct and its regulation by the renin-angiotensin-aldosterone system.

Clin Sci (Lond) 2019 01 8;133(1):75-82. Epub 2019 Jan 8.

Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

Distal nephron of the kidney plays key roles in fluid volume and electrolyte homeostasis by tightly regulating reabsorption and excretion of Na, K, and Cl Studies to date demonstrate the detailed electrolyte transport mechanisms in principal cells of the cortical collecting duct, and their regulation by renin-angiotensin-aldosterone system (RAAS). In recent years, however, accumulating data indicate that intercalated cells, another cell type that is present in the cortical collecting duct, also play active roles in the regulation of blood pressure. Notably, pendrin in β-intercalated cells not only controls acid/base homeostasis, but is also one of the key components controlling salt and K transport in distal nephron. We have recently shown that pendrin is regulated by the co-ordinated action of angiotensin II (AngII) and aldosterone, and at the downstream of AngII, mammalian target of rapamycin (mTOR) signaling regulates pendrin through inhibiting the kinase unc51-like-kinase 1 and promoting dephosphorylation of mineralocorticoid receptor (MR). In this review, we summarize recent advances in the current knowledge on the salt transport mechanisms in the cortical collecting duct, and their regulation by the RAAS.
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http://dx.doi.org/10.1042/CS20180194DOI Listing
January 2019

Epidemiological profiles of chronic low back and knee pain in middle-aged and elderly Japanese from the Murakami cohort.

J Pain Res 2018 12;11:3161-3169. Epub 2018 Dec 12.

Division of Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan,

Purpose: Epidemiological profiles of chronic low back and knee pain have not been studied extensively. This study aimed to determine the prevalence of and potential risk factors associated with chronic low back and knee pain in middle-aged and elderly Japanese.

Methods: This cross-sectional study involved 14,217 community-dwelling individuals aged 40-74 years living in the Murakami area of Japan. A self-administered questionnaire was used to obtain information regarding marital status, education level, occupation, household income, and body size. Participants also reported current chronic pain, if any, by site and degree of severity, using the verbal rating scale of the Short Form 36.

Results: The prevalence of moderate-very severe chronic pain was 9.7% in the low back, 6.7% in the knee, 13.9% in either the low back or knee, and 2.6% in both the low back and knee. Multivariate analysis revealed that lower education level, lower income, and manual occupation in men and older age and higher body mass index in women were significantly associated with a higher prevalence of chronic low back pain. In both sexes, older age, lower education level, and higher body mass index were significantly associated with a higher prevalence of knee pain. Regarding sex differences, adjusted ORs of chronic pain of the low back and knee for women were 0.85 (95% CI 0.75-0.97) and 1.27 (95% CI 1.09-1.49), respectively.

Conclusion: Nearly 14% of middle-aged and elderly individuals had moderate-very severe chronic pain of the low back or knee, and this pain was associated with many demographic factors, including sex, age, education level, household income, occupation, and body size.
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http://dx.doi.org/10.2147/JPR.S184746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296201PMC
December 2018

Modulation of Cl signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT.

Sci Signal 2018 10 30;11(554). Epub 2018 Oct 30.

Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

IRBIT is a multifunctional protein that controls the activity of various epithelial ion transporters including NBCe1-B. Interaction with IRBIT increases NBCe1-B activity and exposes two cryptic Cl-sensing GXXXP sites that enable regulation of NBCe1-B by intracellular Cl (Cl ). Here, phosphoproteomic analysis revealed that IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl Mutational analysis suggested that the phosphorylation status of Ser, Ser, and Ser was regulated by IRBIT and determined whether NBCe1 transporters are in active or inactive conformations. The absence of phosphorylation at Ser, Ser, or Ser produced NBCe1-B in the conformations pSer/pSer, pSer/pSer, or pSer/pSer, respectively. The activity of the pSer/pSer form was similar to that of IRBIT-activated NBCe1-B, but it was insensitive to inhibition by Cl The properties of the pSer/pSer form were similar to those of wild-type NBCe1-B, whereas the pSer/pSer form was partially active, further activated by IRBIT, but retained inhibition by Cl Furthermore, IRBIT recruited the phosphatase PP1 and the kinase SPAK to control phosphorylation of Ser, which affected Cl sensing by the GXXXP motif. IRBIT also recruited the phosphatase calcineurin and the kinase CaMKII to control phosphorylation of Ser, which affected Cl sensing by the GXXXP motif. Ser, Ser, and Ser are conserved in all NBCe1 variants and affect their activity. These findings reveal how multiple kinase and phosphatase pathways use phosphorylation sites to fine-tune a transporter, which have important implications for epithelial fluid and HCO secretion.
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http://dx.doi.org/10.1126/scisignal.aat5018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325875PMC
October 2018

The Murakami Cohort Study of vitamin D for the prevention of musculoskeletal and other age-related diseases: a study protocol.

Environ Health Prev Med 2018 Jun 26;23(1):28. Epub 2018 Jun 26.

Niigata Prefectural Office, 4-1 Shinkocho, Chuo-ku, Niigata, 950-0965, Japan.

Background: Age-related musculoskeletal diseases are becoming increasingly burdensome in terms of both individual quality of life and medical cost. We intended to establish a large population-based cohort study to determine environmental, lifestyle, and genetic risk factors of musculoskeletal and other age-related diseases, and to clarify the association between vitamin D status and such diseases.

Methods: We targeted 34,802 residents aged 40-74 years living in areas of northern Niigata Prefecture, including Sekikawa Village, Awashimaura Village, and Murakami City (Murakami region). The baseline questionnaire survey, conducted between 2011 and 2013, queried respondents on their lifestyle and environmental factors (predictors), and self-reported outcomes. Plasma 25-hydroxyvitamin D (25[OH]D) concentration, an indicator of vitamin D status, was determined with the Liaison® 25OH Vitamin D Total Assay. The primary outcome of this study was osteoporotic fracture; other outcomes included age-related diseases including knee osteoarthritis, perception of chronic pain, dementia, and long-term care insurance use. Mean ages of men and women were 59.2 (SD = 9.3, N = 6907) and 59.0 (SD = 9.3, N = 7457) years, respectively. From the blood samples provided by 3710 men and 4787 women, mean 25(OH)D concentrations were 56.5 (SD = 18.4) nmol/L (22.6 ng/mL) and 45.4 (SD = 16.5) nmol/L (18.2 ng/mL), respectively.

Discussion: Follow-up surveys are planned every 5 years for 15 years, and incident cases of our targeted diseases will be followed at hospitals and clinics in and nearby the cohort area. We anticipate that we will be able to clarify the association between vitamin D status and multiple disease outcomes in a Japanese population.
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http://dx.doi.org/10.1186/s12199-018-0715-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020305PMC
June 2018

Chronic nephritis associated with X-linked thrombocytopenia.

CEN Case Rep 2018 May 16;7(1):187-188. Epub 2018 Mar 16.

Apheresis and Dialysis Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

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http://dx.doi.org/10.1007/s13730-018-0322-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886952PMC
May 2018

A pure chloride channel mutant of CLC-5 causes Dent's disease via insufficient V-ATPase activation.

Pflugers Arch 2016 07 5;468(7):1183-1196. Epub 2016 Apr 5.

Department of Internal Medicine, Faculty of Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Dent's disease is characterized by defective endocytosis in renal proximal tubules (PTs) and caused by mutations in the 2Cl(-)/H(+) exchanger, CLC-5. However, the pathological role of endosomal acidification in endocytosis has recently come into question. To clarify the mechanism of pathogenesis for Dent's disease, we examined the effects of a novel gating glutamate mutation, E211Q, on CLC-5 functions and endosomal acidification. In Xenopus oocytes, wild-type (WT) CLC-5 showed outward-rectifying currents that were inhibited by extracellular acidosis, but E211Q and an artificial pure Cl(-) channel mutant, E211A, showed linear currents that were insensitive to extracellular acidosis. Moreover, depolarizing pulse trains induced a robust reduction in the surface pH of oocytes expressing WT CLC-5 but not E211Q or E211A, indicating that the E211Q mutant functions as a pure Cl(-) channel similar to E211A. In HEK293 cells, E211A and E211Q stimulated endosomal acidification and hypotonicity-inducible vacuolar-type H(+)-ATPase (V-ATPase) activation at the plasma membrane. However, the stimulatory effects of these mutants were reduced compared with WT CLC-5. Furthermore, gene silencing experiments confirmed the functional coupling between V-ATPase and CLC-5 at the plasma membrane of isolated mouse PTs. These results reveal for the first time that the conversion of CLC-5 from a 2Cl(-)/H(+) exchanger into a Cl(-) channel induces Dent's disease in humans. In addition, defective endosomal acidification as a result of insufficient V-ATPase activation may still be important in the pathogenesis of Dent's disease.
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http://dx.doi.org/10.1007/s00424-016-1808-7DOI Listing
July 2016

Intracellular Cl- as a signaling ion that potently regulates Na+/HCO3- transporters.

Proc Natl Acad Sci U S A 2015 Jan 5;112(3):E329-37. Epub 2015 Jan 5.

Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892;

Cl(-) is a major anion in mammalian cells involved in transport processes that determines the intracellular activity of many ions and plasma membrane potential. Surprisingly, a role of intracellular Cl(-) (Cl(-) in) as a signaling ion has not been previously evaluated. Here we report that Cl(-) in functions as a regulator of cellular Na(+) and HCO3 (-) concentrations and transepithelial transport through modulating the activity of several electrogenic Na(+)-HCO3 (-) transporters. We describe the molecular mechanism(s) of this regulation by physiological Cl(-) in concentrations highlighting the role of GXXXP motifs in Cl(-) sensing. Regulation of the ubiquitous Na(+)-HCO3(-) co-transport (NBC)e1-B is mediated by two GXXXP-containing sites; regulation of NBCe2-C is dependent on a single GXXXP motif; and regulation of NBCe1-A depends on a cryptic GXXXP motif. In the basal state NBCe1-B is inhibited by high Cl(-) in interacting at a low affinity GXXXP-containing site. IP3 receptor binding protein released with IP3 (IRBIT) activation of NBCe1-B unmasks a second high affinity Cl(-) in interacting GXXXP-dependent site. By contrast, NBCe2-C, which does not interact with IRBIT, has a single high affinity N-terminal GXXP-containing Cl(-) in interacting site. NBCe1-A is unaffected by Cl(-) in between 5 and 140 mM. However, deletion of NBCe1-A residues 29-41 unmasks a cryptic GXXXP-containing site homologous with the NBCe1-B low affinity site that is involved in inhibition of NBCe1-A by Cl(-) in. These findings reveal a cellular Cl(-) in sensing mechanism that plays an important role in the regulation of Na(+) and HCO3 (-) transport, with critical implications for the role of Cl(-) in cellular ion homeostasis and epithelial fluid and electrolyte secretion.
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http://dx.doi.org/10.1073/pnas.1415673112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311818PMC
January 2015

Regulatory roles of nitric oxide and angiotensin II on renal tubular transport.

World J Nephrol 2014 Nov;3(4):295-301

Shoko Horita, Motonobu Nakamura, Ayumi Shirai, Osamu Yamazaki, Nobuhiko Satoh, Masashi Suzuki, George Seki, Department of Internal Medicine, The University of Tokyo, Tokyo 113-0033, Japan.

Renal tubules regulate blood pressure and humoral homeostasis. Mediators that play a significant role in regulating the transport of solutes and water include angiotensin II (AngII) and nitric oxide (NO). AngIIcan significantly raise blood pressure via effects on the heart, vasculature, and renal tubules. AngII generally stimulates sodium reabsorption by triggering sodium and fluid retention in almost all segments of renal tubules. Stimulation of renal proximal tubule (PT) transport is thought to be essential for AngII-mediated hypertension. However, AngII has a biphasic effect on in vitro PT transport in mice, rats, and rabbits: stimulation at low concentrations and inhibition at high concentrations. On the other hand, NO is generally thought to inhibit renal tubular transport. In PTs, NO seems to be involved in the inhibitory effect of AngII. A recent study reports a surprising finding: AngII has a monophasic stimulatory effect on human PT transport. Detailed analysis of signalling mechanisms indicates that in contrast to other species, the human NO/guanosine 3',5'-cyclic monophosphate/extracellular signal-regulated kinase pathway seems to mediate this effect of Ang II on PT transport. In this review we will discuss recent progress in understanding the effects of AngII and NO on renal tubular transport.
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http://dx.doi.org/10.5527/wjn.v3.i4.295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220364PMC
November 2014

Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome.

Kidney Int 2015 Mar 29;87(3):535-42. Epub 2014 Oct 29.

Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Hyperinsulinemia can contribute to hypertension through effects on sodium transport. To test whether the stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in insulin resistance, we compared the effects of insulin on abdominal adipocytes and proximal tubules in rats and humans. Insulin markedly stimulated the sodium-bicarbonate cotransporter (NBCe1) activity in isolated proximal tubules through the phosphoinositide 3-kinase (PI3-K) pathway. Gene silencing in rats showed that while insulin receptor substrate (IRS)1 mediates the insulin effect on glucose uptake into adipocytes, IRS2 mediates the insulin effect on proximal tubule transport. The stimulatory effect of insulin on glucose uptake into adipocytes was severely reduced, but its stimulatory effect on NBCe1 activity was completely preserved in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and patients with insulin resistance. Despite widespread reduction of IRS1 and IRS2 expression in insulin-sensitive tissues, IRS2 expression in the kidney cortex was exceptionally preserved in both OLETF rats and patients with insulin resistance. Unlike liver, acute insulin injection failed to change the expression levels of IRS2 and sterol regulatory element-binding protein 1 in rat kidney cortex, indicating that regulatory mechanisms of IRS2 expression are distinct in liver and kidney. Thus, preserved stimulation of proximal tubule transport through the insulin/IRS2/PI3-K pathway may play an important role in the pathogenesis of hypertension associated with metabolic syndrome.
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http://dx.doi.org/10.1038/ki.2014.351DOI Listing
March 2015

Roles of renal proximal tubule transport in acid/base balance and blood pressure regulation.

Biomed Res Int 2014 28;2014:504808. Epub 2014 May 28.

Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Sodium-coupled bicarbonate absorption from renal proximal tubules (PTs) plays a pivotal role in the maintenance of systemic acid/base balance. Indeed, mutations in the Na(+)-HCO3 (-) cotransporter NBCe1, which mediates a majority of bicarbonate exit from PTs, cause severe proximal renal tubular acidosis associated with ocular and other extrarenal abnormalities. Sodium transport in PTs also plays an important role in the regulation of blood pressure. For example, PT transport stimulation by insulin may be involved in the pathogenesis of hypertension associated with insulin resistance. Type 1 angiotensin (Ang) II receptors in PT are critical for blood pressure homeostasis. Paradoxically, the effects of Ang II on PT transport are known to be biphasic. Unlike in other species, however, Ang II is recently shown to dose-dependently stimulate human PT transport via nitric oxide/cGMP/ERK pathway, which may represent a novel therapeutic target in human hypertension. In this paper, we will review the physiological and pathophysiological roles of PT transport.
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http://dx.doi.org/10.1155/2014/504808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058521PMC
February 2015

Postoperative outcomes of primary hepatic neuroendocrine carcinomas: review article.

Osaka City Med J 2013 Dec;59(2):105-13

Department of Surgery, Osaka City Juso General Hospital, Japan.

Background: We examined the course of a primary hepatic neuroendocrine carcinoma (PHNEC) patient and analyzed the postoperative outcome of all reported PHNEC cases.

Methods: A literature search for PHNEC cases was performed using PubMed. All reported cases and our present patient were analyzed in this study. Survival analysis was performed using the Kaplan-Meier method. Risk factors for the recurrence of PHNEC following hepatic resection were investigated.

Results: A total of 43 patients were analyzed in this study. The 3-, 5-, and 7-year overall survival rates were 55%, 48%, and 48%, respectively. The 3-, 5-, and 7-year overall survival rates in surgery patients were 78% each, and 25%, 17%, and 17%, respectively in nonsurgery patients. Lymph node metastasis posed a significant risk factor for postoperative recurrence.

Conclusions: Hepatic surgery is an appropriate therapeutic treatment for PHNEC without distant metastasis nor lymph node metastasis. Adjuvant chemotherapy might be necessary for PHNEC patients with lymph node metastases.
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December 2013

Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway.

J Am Soc Nephrol 2014 Jul 7;25(7):1523-32. Epub 2014 Feb 7.

Departments of Internal Medicine and

Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT1)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.
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http://dx.doi.org/10.1681/ASN.2013060596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073427PMC
July 2014

Molecular mechanisms of renal and extrarenal manifestations caused by inactivation of the electrogenic Na(+)-HCO3 (-) cotransporter NBCe1.

Front Physiol 2013 Oct 1;4:270. Epub 2013 Oct 1.

Department of Internal Medicine, School of Medicine, The University of Tokyo Tokyo, Japan.

The electrogenic Na(+)-HCO3 (-) cotransporter NBCe1 plays an essential role in bicarbonate absorption from renal proximal tubules, but also mediates the other biological processes in extrarenal tissues such as bicarbonate secretion from pancreatic ducts, maintenance of tissue homeostasis in eye, enamel maturation in teeth, or local pH regulation in synapses. Homozygous mutation in NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as short stature, ocular abnormalities, enamel abnormalities, and migraine. Functional analyses of NBCe1 mutants using different expression systems suggest that at least a 50% reduction of the transport activity may be required to induce severe pRTA. In addition to functional impairments, some NBCe1 mutants show trafficking defects. Some of the pRTA-related NBCe1 mutants showing the cytoplasmic retention have been shown to exert a dominant negative effect through hetero-oligomer complexes with wild-type NBCe1 that may explain the occurrence of extrarenal manifestations in the heterozygous carries of NBCe1 mutations. Both NBCe1 knockout (KO) and W516X knockin (KI) mice showed very severe pRTA and reproduced most of the clinical manifestations observed in human pRTA patients. Functional analysis on isolated renal proximal tubules from W516X KI mice directly confirmed the indispensable role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we will focus on the molecular mechanisms underling the renal and extrarenal manifestations caused by NBCe1 inactivation.
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http://dx.doi.org/10.3389/fphys.2013.00270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787273PMC
October 2013

Identification of dominant negative effect of L522P mutation in the electrogenic Na⁺-HCO₃⁻ cotransporter NBCe1.

Pflugers Arch 2013 Sep 5;465(9):1281-91. Epub 2013 Apr 5.

Department of Internal Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Homozygous mutations in the electrogenic Na(+)-HCO3 (-) cotransporter NBCe1 cause proximal renal tubular acidosis (pRTA) associated with extrarenal manifestations such as ocular abnormalities and migraine. Previously, the NBCe1 cytosolic mutant S982NfsX4 was shown to have a dominant negative effect by forming hetero-oligomer complexes with wild type (WT), which might be responsible for the occurrence of glaucoma and migraine in the heterozygous family members. In this study, we investigated whether the NBCe1 L522P mutant has a similar dominant negative effect. Functional analyses in Xenopus oocytes and HEK293 cells revealed that the L522P mutant had no transport activity due to defective membrane expression. Furthermore, when coexpressed with WT, L522P significantly reduced the transport activity of WT. In HEK293 cells, the cytosolic mutant L522P reduced the membrane expression of NBCe1 by forming hetero-oligomer complexes with WT. Among the artificial Leu(522) mutants, L522I showed proper membrane expression and normal transport activity. However, the other mutants L522R, L522K, L522D, and L522E showed a predominant cytosolic retention. Moreover, L522R had a dominant negative effect, when coexpressed with WT. These results indicate that Leu(522) plays an important role in the structure and trafficking of NBCe1. They also suggest that the NBCe1 mutants retaining in cytoplasm may have the dominant negative effect in common, which may induce some clinical manifestations.
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http://dx.doi.org/10.1007/s00424-013-1277-1DOI Listing
September 2013

[Two long-term survival cases of unresectable intrahepatic cholangiocarcinoma treated with hepatic arterial infusion chemotherapy and radiation therapy].

Gan To Kagaku Ryoho 2012 Nov;39(12):2006-8

Dept. of Hepato-Biliary-Pancreatic Surgery and Gastroenterological Surgery, Osaka City General Hospital, Japan.

The prognosis for patients with unresectable intrahepatic cholangiocarcinoma(ICC) is extremely poor. Case 1 was a 65- year-old woman who had an ICC of 9 cm in diameter (mass-forming type) in the right lobe with portal trunk invasion. She was treated with hepatic arterial infusion chemotherapy[cisplatin(CDDP)/5-fluorouracil(5-FU)/l-leucovorin(l-LV)] and radiation therapy (total dose, 50 Gy). After 6 months, abdominal computed tomography (CT) revealed that the tumor had regressed. She survived for 7 years without recurrence of the ICC; subsequently, she died of peritoneal cancer. Case 2 was a 59-year-old woman who had an ICC of 8 cm in diameter (mass-forming type) in the left lobe with lymph node metastasis in the hepatoduodenal ligament; the right hepatic artery was involved by the metastatic lymph nodes. She was treated with hepatic arterial infusion chemotherapy(CDDP/5-FU/l-LV) and radiation therapy(total dose, 30 Gy). After 10 months, abdominal CT revealed that the tumor had disappeared, but paraaortic and mediastinal lymph node metastases were detected. She was therefore treated with systemic chemotherapy. Treatment with systematic chemotherapy enabled her to survive for over 5 years with a good performance status.
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November 2012
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