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Collagen type VI (COL6) deposition occurs in various glomerular diseases, causing serious pathological damage like nodular lesions. However, the mechanisms underlying the deposition of COL6 remain unclear. In renal biopsy samples, immunohistochemical analyses revealed that COL6 and phosphorylated histone H2AX (γ-H2AX), a DNA damage marker, were detected mainly in diabetic nodular glomerulosclerosis, in which the γ-H2AX-positive area was identified as the independent factor significantly associated with the COL6-positive area (β: 0.539, t = 2.668). In in vitro studies, COL6 secretion from human renal glomerular endothelial cells (HRGECs) was assessed by measuring the decrease in the cytoplasmic COL6-positive cells and an increase in the amount of COL6 in the culture medium. Mitomycin C (MMc) treatment of HRGECs increased the number of γ-H2AX-positive cells and COL6 secretion, which were suppressed by a specific inhibitor of ataxia telangiectasia and Rad3-related (ATR). MMc-induced COL6 secretion was also suppressed by Annexin A2 (ANXA2) siRNA transfection. Moreover, the inhibition of ATR activity did not induce any extra suppression in the MMc-induced COL6 secretion by ANXA2 siRNA transfected cells. These results confirm that nodular glomerulosclerosis partially results from DNA damage in the glomerulus and that DNA damage-induced COL6 secretion from HRGECs occurs through an ATR and ANXA2-mediated pathway.

Although it has been reported that chronic kidney disease exacerbates sarcopenia progression, the mechanisms of the process remain unclear. Fifty-one patients who underwent renal transplantation at our hospital since 1998 (31 males and 20 females; aged 29–52 years at the time of transplantation) were retrospectively examined for the relationships among the psoas muscle index (PMI), intramuscular adipose tissue content (IMAC), serum adiponectin fractions (high-/low-molecular-weight) and new-onset diabetes after transplantation (NODAT). Before transplantation, age at kidney transplantation negatively correlated with PMI and positively correlated with IMAC (rS = − 0.427, p

In coronavirus disease 2019 pneumonia, a cytokine storm resulting from an excessive inflammatory response to the viral infection is thought to play a role in the exacerbation of the pneumonia and its prognosis. Favipiravir and ciclesonide are not effective in the inhibition of the cytokine storm. In this case report, we describe the experience of tocilizumab administration and polymyxin B immobilized fiber direct hemoperfusion in severe coronavirus disease 2019 pneumonia patient. A 52-year-old man presented with fever and dyspnea and was diagnosed with coronavirus disease 2019 pneumonia based on a polymerase chain reaction test. Mechanical ventilation and favipiravir administration were started for respiratory failure. However, favipiravir could not be continued due to hepatic dysfunction. Consequently, tocilizumab was administered, and continuous hemodiafiltration and endotoxin adsorption therapy (polymyxin B immobilized fiber direct hemoperfusion) were performed for acute renal failure. C-reactive protein decreased from 44 to 3.52 mg/dL, and the patient’s respiratory status improved over time, enabling mechanical ventilation to be withdrawn. This case indicates that adding polymyxin B immobilized fiber direct hemoperfusion to tocilizumab administration may further increase efficacy in coronavirus disease 2019 treatment; however, more case–control studies are needed.

Aim Conclusions regarding the best rituximab (RTX) dose to maintain remission and reduce immunosuppressant dependence in adult patients with steroid-dependent minimal change nephrotic syndrome (MCNS) are inconsistent. We report the first low-dose (l 375 mg/m2 BSA) RTX therapy, administered once every 6 months. Materials and methods In this retrospective single-arm cohort study, we investigated the safety and efficacy of low-dose RTX therapy to reduce and ultimately stop prednisolone (PSL) and cyclosporine (CyA) treatment. 13 patients (8 men and 5 women; aged 16 - 65 years; 8-year median treatment history; 12 patients concurrently taking CyA) with steroid-dependent MCNS were chosen to maintain remission following low-dose RTX (200 mg/body) administration. Results The median period of subject observation following the first RTX dosing was 34 months (cumulative RTX dose: 400 - 1,400 mg). RTX significantly reduced PSL and CyA doses during the final observation in each subject (median dose: PSL 15→0 mg/day, p = 0.0002; CyA 80→0 mg/day, p = 0.0005). All patients maintained complete remission after discontinuing both drugs for a median complete remission (CR) maintenance period of 25 months. One patient showed relapse following the first RTX dose, but a temporary increase in PSL and CyA dose restored the remission. No serious RTX-related adverse effects were observed. Even with MCNS remission, peripheral CD19-positive cell count was not depleted in 90.5% of all cases. Conclusion Low-dose RTX therapy appears to be effective in maintaining remission and reducing immunosuppressant doses in patients with steroid-dependent MCNS, which might involve a B-cell-independent mechanism.

Background and Aims A hypothesis has been proposed that serum (s-) soluble urokinase receptor (suPAR) activates glomerular podocyte β3 integrin to cause podocyte injury and onset of proteinuria in primary nephrotic syndrome (pNS). However, s-suPAR has been questioned as a disease marker for pNS because it did not correlate with urinary protein (UP). Furthermore, there are a few reports that suggested a correlation between urinary (u-) suPAR and UP by univariate analysis, but the correlation between the two has not been studied by multivariate analysis taking confounding factors into account. In addition, it is unclear how u-suPAR is involved in the pathogenesis of pNS. Method In 36 patients with pNS including minimal change (n=18), focal segmental glomerulosclerosis (n=7), membranous nephropathy (n=9) and membranoproliferative glomerulonephritis (n=2), the relationship between u-suPAR (pg/mgCr) and UP (g/gCr) was examined by cross-sectional analysis of baseline values before treatment and longitudinal analysis of changes during the first 2 months of treatment (⊿). In addition, the localization and staining intensity of activated β3 integrin in renal tissue were examined by immuno-histochemistry methods. We also examined whether s-suPAR (pg/ml) or u-suPAR is useful for predicting renal prognosis (1.5-fold increase from baseline in s-Cr) using Cox proportional hazard analysis. Results In cross-sectional analysis, u-suPAR was a UP predictor independent of s-suPAR, eGFR and selectivity index (S.I.) [standardized partial regression coefficient (stdβ) = 0.879, p Conclusion In pNS, u-suPAR was a proteinuria predictor independent of s-suPAR, suggesting the possibility of the mechanisms of proteinuria through β3 integrin activation in PTBB by u-suPAR. In addition, s-suPAR was useful in predicting renal prognosis.

Background and Aims Although it is reported that chronic kidney disease participates some roles in progression of sarcopenia, mechanisms of the progression of sarcopenia are unclear so far. In this observational study, we focused on serum adiponectin levels, that is a marker of metabolic syndrome, cardiovascular disease, and skeletal muscle mass in patients with kidney transplantation. Method Fifty-one patients who underwent renal transplantation at our hospital in and after 1998 (31 males and 20 females; aged 29-52 years at the time of transplantation) were retrospectively examined the relationships between the psoas muscle index (PMI), intramuscular adipose tissue content (IMAC), serum adiponectin fractions (high-/low-molecular-weight), and new-onset diabetes after transplantation (NODAT). Results Age at kidney transplantation negatively correlated with PMI before transplantation and positively correlated with IMAC before transplantation (rS=-0.427, p Conclusion PMI increased associated with high-molecular-weight adiponectin levels after renal transplantation. In addition, PMI increased suppressed the development of NODAT.

DNA methylation is a common method of gene expression regulation, and this form of regulation occurs in the neurodevelopmental disorder Prader-Willi syndrome (PWS). Gene expression regulation via methylation is important for humans, although there is little understanding of the role of methylation in neuronal differentiation. We characterized the cellular differentiation potential of iPS cells derived from a patient with PWS with abnormal methylation (M-iPWS cells). A comparative genomic hybridization (CGH) array revealed that, unlike iPWS cells (deletion genes type), the abnormally methylated M-iPWS cells had no deletion in the15q11.2-q13 chromosome region. In addition, methylation-specific PCR showed that M-iPWS cells had strong methylation in CpG island of the small nuclear ribonucleoprotein polypeptide N (SNRPN) on both alleles. To assess the effect of abnormal methylation on cell differentiation, the M-iPWS and iPWS cells were induced to differentiate into embryoid bodies (EBs). The results suggest that iPWS and M-iPWS cells are defective at differentiation into ectoderm. Neural stem cells (NSCs) and neurons derived from M-iPWS cells had fewer NSCs and mature neurons with low expression of NSCs and neuronal markers. We conclude that expression of the downstream of genes in the PWS region regulated by methylation is involved in neuronal differentiation.

This study investigated the effect of a driver-training tool that uses “HazardTouch” software and videos of actual accidents on drivers’ eye fixation through a tablet device (iPad). Drivers’ eye fixation of a video of a car passing thirteen intersections without signals was measured before and after training, using an eye-mark recorder. Three training exposures of four scenes using HazardTouch improved drivers’ eye fixation on the stimulus movie. In particular, the first fixation on the edge of the blind spot at intersections appeared significantly sooner after training. Moreover, fixation frequency for this blind spot increased significantly at post-training. These results suggest that the proposed driver-training tool effectively improves eye-fixation behavior in drivers and may prevent accidents.

DNA methylation is a common method of gene expression regulation, and this form of regulation occurs in the neurodevelopmental disorder Prader Willi syndrome (PWS). Gene expression regulation via methylation is important for humans, although the role of methylation in neuronal differentiation is unknown. We characterized the cellular differentiation potential of iPS cells derived from a patient with PWS with abnormal methylation (M-iPWS cells). A CGH array revealed that, unlike iPWS cells, the abnormally methylated M-iPWS cells had no deletion in the15q11.2-q13 chromosome region. In addition, methylation-specific PCR showed that M-iPWS cells had strong methylation of the SNRPN CpG island. To assess the effect of abnormal methylation on cell differentiation, the M-iPWS cells and iPWS cells were induced to differentiate into embryoid bodies, which contain endoderm, mesoderm, and ectoderm. The results suggest that iPS cells from patients with PWS are defective at differentiation into ectoderm. When directionally differentiated into neuronal cells, the expression of neural stem cells (NSCs) markers in M-iPWS cells was relatively low compared to those from control cells. Nestin and Musashi-1 immunoreactivity was also low in NSCs from M-iPWS cells. MAP2 and βIII-tubulin immunoreactivity was also sparse, and marker expression was low in neuronal cells differentiated from M-iPWS cells. We conclude that abnormal methylation in the PWS region is involved in neuronal differentiation.

Vitronectin, an extracellular matrix protein, controls the differentiation of cerebellar granule cell precursors (CGCPs) via αvβ5 integrin, particularly in the initial stage of differentiation to granule cells. In this study, we determined whether vitronectin regulates axon specification in this initial differentiation stage of CGCPs. First, we analyzed whether vitronectin deficiency, β5 integrin knockdown (KD), and β5 integrin overexpression affect axon specification of primary cultured CGCPs. Vitronectin deficiency and β5 integrin KD inhibited axon formation, while vitronectin administrated- and β5 integrin overexpressed-neurons formed multiple axons. Moreover, KD of β5 integrin suppressed vitronectin-induced multiple axon formation. These findings indicate that vitronectin contributes to regulating axon specification via αvβ5 integrin in CGCPs. Next, we determined the signaling pathway involved in regulating vitronectin-induced axon specification. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), inhibited vitronectin-induced multiple axon specification, and lithium chloride, an inhibitor of glyocogen synthase kinase 3 beta (GSK3β), attenuated the inhibitory effect of vitronectin-KO and β5 integrin KD on the specification of CGCPs. In addition, vitronectin induced the phosphorylation of protein kinase B (Akt) and GSK3β in neuroblastoma Neuro2a cells. Taken together, our results indicate that vitronectin plays an important factor in axon formation process in CGCPs via a β5 integrin/PI3K/GSK3β pathway.

Sirtuin involves in cellular processes to adapt to starvation in the endocrine and metabolic systems. We examined Sir2B function during early Dictyostelium development upon starvation. GFP-tagged Sir2B was expressed and the immunoreactivity was detected a punctate pattern near cell surface. Sir2B mRNA was expressed in vegetative cells and peaked at 2 h after starvation. Ectopic expression of Sir2B enhanced aggregate formation with increased expressions of cell adhesion molecules such as cadA, csaA, TgrB1, and TgrC1 at 8h compared to those in control cells. Sir2B null-mutant cells (Sir2B KO cells) were generated and they formed aggregates smaller than those of wild-type cells after 24 h. Because cell-cell adhesion affects aggregation size, cell cohesion assay of Sir2B KO cells showed cell-cell adhesion impairment at 8 and 10 h during development, and the expressions of four cell adhesion molecules were reduced in Sir2B KO cells compared to wild-type cells until 8 h after starvation. When RNAi-mediated cadA or csaA knockdown cells (cadA KD or csaA KD cells) were generated, csaA KD cells formed smaller aggregates and affected the expressions of other cell adhesion molecules to reduce, but cadA KD cells did not show to affect aggregation size and cell adhesion molecules expressions apparently. These results suggest that Sir2B is involved in csaA expression and affects other cell adhesion molecules during early development upon starvation.