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Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy. [ABSTRACT FROM AUTHOR]

Elevation of total cell-free DNA (cfDNA) in patients with preeclampsia is well-known; however, whether this change precedes the onset of symptoms remains inconclusive. Here, we conducted a nested case–control study to determine the elevation of cfDNA levels in women who subsequently developed preeclampsia. Methylated HYP2 (m-HYP2) levels were determined in 68 blood samples collected from women with hypertensive disorders of pregnancy, along with 136 control samples, using real-time quantitative PCR. The measured m-HYP2 levels were converted to multiples of the median (MoM) values for correction of maternal characteristics. The m-HYP2 levels and MoM values in patients with preeclampsia were significantly higher than in controls during the third trimester (P < 0.001, both), whereas those for women who subsequently developed preeclampsia did not differ during the second trimester. However, when patients with preeclampsia were divided based on the onset-time of preeclampsia or 10th percentile birth weight, both values were significantly higher in women who subsequently developed early-onset preeclampsia (P < 0.05, both) and preeclampsia with small-for-gestational-age (SGA) neonate (P < 0.01, both) than controls. These results suggested that total cfDNA levels could be used to predict early-onset preeclampsia or preeclampsia with SGA neonate. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the association between anti-angiogenic factor soluble c-Met (sMet) concentrations in maternal plasma and the risk of preeclampsia. Methods: The pregnant women included in this study (1) had subsequent preeclampsia ( n = 52) and were compared to normal controls ( n = 104) at the time of amniocentesis (15-20 weeks); and (2) had preeclampsia ( n = 63) and were compared to normal controls ( n = 112) at the time of diagnosis of preeclampsia (29-40 weeks). sMet concentrations were measured by ELISA. Non-parametric statistics were used for analysis. Results: Maternal plasma sMet concentrations were significantly higher in both women with subsequent preeclampsia (median: 1372.7 ng/ml versus 1100.5 ng/ml; p = 0.036) and women with preeclampsia (median: 1651.9 ng/ml versus 1364.7 ng/ml; p < 0.001) than in the controls. After adjusting for potential confounding factors, the risks of developing preeclampsia were as follows: adjusted odds ratio 2.5 (95% confidence interval, 1.2-5.2; p = 0.016) for second trimester sMet concentration with a cut-off value of 1223.5 ng/ml and 4.4 (95% confidence interval, 2.2-9.1; p < 0.001) for third trimester sMet concentration with a cut-off value of 1460.3 ng/ml. Conclusion: Elevated maternal plasma sMet concentrations were independently associated with the increased risk of preeclampsia. [ABSTRACT FROM AUTHOR]

Catechol-O-methyltransferase (COMT) and cytochrome P450c17α (CYP17A1) are key enzymes involved in the metabolism of steroid hormones; genetic polymorphisms in these genes affect enzyme activity. Recently, functional polymorphisms in the COMT and CYP17A1 genes have been suggested as a susceptible marker for intrauterine fetal growth restriction, a typical complication of preeclampsia. Moreover, a close association between COMT and preeclampsia was reported. We therefore investigated the relationships between COMT and CYP17A1 polymorphisms and the risk of preeclampsia.A total of 164 preeclamptic women and 182 normotensive women were enrolled. COMT (Val158Met) and CYP17A1 (-34T/C) polymorphisms were genotyped by quantitative fluorescent-polymerase chain reaction. Multiple logistic regression analysis was used to estimate the risks of preeclampsia according to genotypes.The adjusted odds ratios (adjOR) for the risks of preeclampsia, severe preeclampsia and preeclampsia for small-for-gestational-age (SGA) infants were 1.97 [95% confidence interval (CI): 1.02-3.83], 3.29 (95% CI: 1.60-6.77), and 4.05 (95% CI: 1.78-9.22), respectively, in women homozygous for the variant COMT allele. No significant differences were observed between the two groups with respect to CYP17A1 polymorphisms, indicating that variants of this gene have no effects on preeclampsia. The highest risks of preeclampsia were found among women with homozygous variant genotypes of both genes [adjOR (95% CI): 4.58 (1.92-22.81)]. Moreover, the adjOR for preeclamptic complications in those women was 5.09 (95% CI: 1.93-27.88) for severe preeclampsia and 15.65 (95% CI: 3.19-76.82) for SGA preeclampsia.These findings suggest that homozygosity for the variant allele of the maternal COMT gene may increase susceptibility to preeclampsia. [ABSTRACT FROM AUTHOR]