Souma T.,Tohoku University |
Nezu M.,Tohoku University |
Nakano D.,Tohoku University |
Yamazaki S.,Tohoku University |
And 9 more authors.
Journal of the American Society of Nephrology | Year: 2016
Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein fromamodified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition tomyofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1,PHD2, andPHD3) selectively inEpo-producingcells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs. Copyright © 2016 by the American Society of Nephrology.
Kunikata H.,Tohoku University |
Aizawa N.,Tohoku University |
Kudo M.,Endocrinology and Vascular Medicine |
Mugikura S.,Tohoku University |
And 9 more authors.
PLoS ONE | Year: 2015
Purpose Recent studies have shown that the risk of cerebro- and cardiovascular events (CVEs) is higher in patients with primary aldosteronism (PA) than in those with essential hypertension (EH), and that silent brain infarction (SBI) is a risk factor and predictor of CVEs. Here, we evaluated the relationship between findings from laser speckle flowgraphy (LSFG), a recently introduced non-invasive means of measuring mean blur rate (MBR), an important biomarker of ocular blood flow, and the occurrence of SBI in patients with PA. Methods 87 PA patients without symptomatic cerebral events (mean 55.1 ± 11.2 years old, 48 male and 39 female) were enrolled in this study. We measured MBR in the optic nerve head (ONH) with LSFG and checked the occurrence of SBI with magnetic resonance imaging. We examined three MBR waveform variables: skew, blowout score (BOS) and blowout time (BOT). We also recorded clinical findings, including age, blood pressure, and plasma aldosterone concentration. Results PA patients with SBI (15 of 87 patients; 17%) were significantly older and had significantly lower BOT in the capillary area of the ONH than the patients without SBI (P = 0.02 and P = 0.03, respectively). Multiple logistic regression analysis revealed that age and BOT were independent factors for the presence of SBI in PA patients (OR, 1.15, 95% CI 1.01 - 1.38; P = .03 and OR, 0.73, 95% CI 0.45-0.99; P = .04, respectively). Conclusion PA patients with SBI were older and had lower MBR BOT than those without SBI. Our analysis showed that age was a risk factor for SBI, and that BOT was a protective factor, in patients with PA. This suggests that BOT, a non-invasive and objective biomarker, may be a useful predictor of SBI and form part of future PA evaluations and clinical decision-making. © 2015 Kunikata et al.
Ifuku M.,Fukuoka University |
Miyake K.,Fukuoka University |
Watanebe M.,Fukuoka University |
Ito K.,Fukuoka University |
And 7 more authors.
American Journal of Nephrology | Year: 2013
Background: Kidney disease is characterized by injurious immune responses to self or foreign antigens. The development and maintenance of immune responses generally involves activation of T lymphocytes. We evaluated mRNA expression patterns of T-cell cytokines to identify the principal Th-cell subset involved in the development of antineutrophil cytoplasmic antigen-associated pauci-immune crescentic glomerulonephritis (ANCAGN), membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy (MN). Methods: Kidney biopsy specimens from ANCAGN (17), MPGN (11), and MN (14) patients were evaluated for mRNA expression of various T-cell cytokines. Results: Interferon-γ mRNA expression was detected in both ANCAGN and MPGN, but not in MN patients. Furthermore, mRNA expression of interleukin (IL)-12, a Th1-associated cytokine, was lower in MN patients than in ANCAGN and MPGN patients. In contrast, a significantly higher expression of IL-4 and IL-5 was observed in MN than in ANCAGN and MPGN patients. In the analyses of Th17-associated cytokine expression, a significantly higher expression of IL-6 and IL-17 was observed in ANCAGN than in MPGN and MN patients. No significant differences were observed in the expression of these cytokines between MPGN and MN patients. With regard to Treg-associated cytokines, a significantly higher IL-10 expression was observed in MN than in ANCAGN patients, and a significantly higher transforming growth factor-β expression was observed in MN than in ANCAGN and MPGN patients. Similarly, Foxp3 expression was significantly higher in MN. Conclusion: Th1 and Th17 immune responses in ANCAGN, the Th1 response in MPGN, and Th2 and Treg responses in MN patients may be integral for the distinct histological features of these diseases. Copyright © 2013 S. Karger AG, Basel.
Mishima E.,Endocrinology and Vascular Medicine |
Mishima E.,Tohoku University |
Fukuda S.,Keio University |
Fukuda S.,RIKEN |
And 15 more authors.
Journal of the American Society of Nephrology | Year: 2015
The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) onCKD. Oral administration of lubiprostone (500 mg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresismass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment. © 2015 by the American Society of Nephrology.
Souma T.,Tohoku University |
Yamazaki S.,Tohoku University |
Moriguchi T.,Tohoku University |
Suzuki N.,United Centers for Advanced Research and Translational Medicine |
And 10 more authors.
Journal of the American Society of Nephrology | Year: 2013
CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFkB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracingmethod thatmarked current and/or previous Epo-producing cells and revealed that themajority of myofibroblasts are derived from REPs. Genetic induction of NFkB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFkB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD. Copyright © 2013 by the American Society of Nephrology.
PubMed | Erasmus Medical Center and Endocrinology and Vascular Medicine
Type: | Journal: Muscle & nerve | Year: 2016
No data are available for normative values of cutaneous threshold and spatial discrimination of the feet. We developed clinically applicable reference values in relation to the nerve distributions of the feet.We determined foot sensation in 196 healthy individuals. Cutaneous threshold (1-point static discrimination, S1PD) was tested with monofilaments (0.008 to 300 gram) and spatial discrimination [2-point static and moving discrimination (S2PD, M2PD)] on 5 locations per foot.There was a significant age-dependent increase in S1PD, S2PD, and M2PD values (P<0.05). No significant differences were found between both feet. S1PD values differed up to 0.8 g between genders. There were no significant differences between genders for S2PD and M2PD measurements. M2PD values were generally lower than S2PD values.This study provides age-related normative values for foot sensation to help clinicians assess sensory deficits in relation to aging and identify patients with underlying nerve problems. This article is protected by copyright. All rights reserved.