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Plasminogen activator inhibitor-type 1 (PAI-1) is thought to be profibrotic by inhibiting plasmin generation, thereby decreasing turnover of pathological extracellular matrix (ECM). A mutant, noninhibitory PAI-1 (PAI-1R) was recently shown by us to increase glomerular plasmin generation and reduce disease in anti-thy-1 nephritis. Here, in vitro and in vivo studies were performed to determine whether enhanced plasmin-dependent ECM degradation underlies the therapeutic effect of PAI-1R. 3H-labeled ECM was produced by rat mesangial cells (MCs). The effect of wild-type PAI-1 (wt-PAI-1) and PAI-1R on ECM degradation by newly plated MCs was measured by the release of 3H into medium. In vivo, anti-thy-1 nephritis was assessed in normal, untreated diseased and PAI-1R treated rats with or without the plasmin/plasminogen inhibitor, tranexamic acid (TA). wt-PAI-1 totally inhibited plasmin generation and reduced ECM degradation by 76% when exogenous plasminogen was added. Although PAI-1R alone had no effect, PAI-1R in the presence of wt-PAI-1 reversed the wt-PAI-1 inhibition of ECM degradation in a time- and dose-dependent manner (P<0.001). Plasmin activity and zymography were consistent with ECM degradation. Plasmin inhibitors: α2-antiplasmin, aprotinin, and TA completely blocked PAI-1R's ability to normalize ECM degradation (P<0.001). Consistent with the in vitro results, TA reversed PAI-1R-induced reductions in glomerular fibrin and ECM accumulation. Other measures of disease severity were either unaltered or partially reversed. PAI-1R reduces pathological ECM accumulation, in large part through effectively competing with native PAI-1 thereby restoring plasmin generation and increasing plasmin-dependent degradation of matrix components.Kidney International (2006) 70, 515–522. doi:10.1038/sj.ki.5000353; published online 21 June 2006 [ABSTRACT FROM AUTHOR]

Objective: In patients with congenital heart disease, comprehensive, segment-specific analysis of cardiac anatomy has become 'the standard of care', largely as a result of improvements in cardiac imaging technology. Our aim was to apply segment-specific standards to assess the accuracy of fetal echocardiography. Methods: This was a retrospective review of all fetal echocardiograms (n = 915) performed at our center between August 1998 and June 2003. Of these, 100 studies had congenital heart disease findings and corresponding postnatal studies on the same patients for comparison. An expert independent pediatric echocardiologist, using the standards of accuracy expected of postnatal echocardiography, assessed the studies for the following cardiac segments: abdominal situs, systemic venous return (VR), pulmonary VR, atria, atrioventricular valves, ventricular septum, ventricular hypoplasia, ventricular morphology, semilunar valves, great arterial relation and aortic arch. Sensitivity, specificity, and positive and negative predictive values were calculated for each segment. Results: Specificity and negative predictive value were high for all cardiac segments (range, 82-100%). Sensitivity and positive predictive value were similarly high (range, 83-100%) for most cardiac segments, but were only 50-88% for systemic VR, pulmonary VR and aortic arch segments. Conclusions: Fetal echocardiography has excellent diagnostic accuracy in describing intracardiac anatomy. However, despite both technological advances and improved physician awareness, assessment of systemic VR, pulmonary VR, and aortic arch anatomy remain challenging. [ABSTRACT FROM AUTHOR]

Circulating immune complexes have been described in viral hepatitis and primary biliary cirrhosis but their significance is unclear. Seventy-three patients with acute and chronic liver diseases were evaluated to determine the specificity of immune complex detection for a given liver disease. Immune complexes were measured by the fluid- and solid-phase Clq-binding assays. They were demonstrated frequently in all patients with liver disease, including those with viral hepatitis, alcoholic cirrhosis, chronic active and persistent hepatitis, drug-induced hepatitis and hepatic metastases. The presence of immune complexes was not specific for a given type of liver disease and did not correlate with hepatic dysfunction. We conclude that the detection of immune complexes is of no apparent diagnostic use in liver disease. Further evaluation of the antigen antibody composition would be required to determine any pathogenic significance of the detected circulating immune complexes. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions Image quality of fetal echocardiography (FE) has improved in the recent era, but few recent studies have reported the accuracy of FE, specifically in single ventricle (SV) congenital heart disease (CHD). This study aimed to assess the ability of FE to correctly predict SV‐CHD postnatal anatomy and physiology in a contemporary cohort.The contemporary clinical reports of patients with SV‐CHD, in which FE was performed between July 2017 and July 2021, were compared with postnatal echocardiograms from a formal quality assurance program. SV fetuses were grouped by anatomical subtype. Diagnostic errors were designated as major if the error would have caused significant alteration in parental counseling or postnatal management. The remaining errors were classified as minor. Physiological discrepancies, including prostaglandin‐E (PGE) dependency, atrioventricular valve regurgitation (AVVR), pulmonary venous obstruction, and restrictive atrial septum (RAS) were assessed by chart review of the postnatal course.A total of 119 subjects were analyzed. SV subtypes in the cohort included hypoplastic left heart syndrome (HLHS) (n = 68), tricuspid atresia (n = 16), double‐inlet left ventricle (n = 12), unbalanced atrioventricular canal (UAVC) (n = 11), heterotaxy (n = 9) and other (n = 3). The rate of major anatomical and physiological errors was low (n = 6 (5.0%)). A higher proportion of minor errors was noted in HLHS and tricuspid atresia, but the differences were not statistically significant. Physiological discrepancies were uncommon, with three major discrepancies, including underestimation of the degree of venous obstruction in one non‐HLHS fetus with total anomalous pulmonary venous return, overestimation of RAS in one HLHS fetus and incorrect prediction of PGE dependency in one case false‐negative for pulmonary blood flow. No discrepancy in degree of AVVR or RAS affected postnatal care. Minor physiological discrepancies included two false‐positive predictions of PGE dependency with one false‐positive for ductal‐dependent systemic flow and one false‐positive for pulmonary blood flow.In this contemporary review of FE at our center, there was high accuracy in describing anatomical and physiological findings in SV‐CHD. Major physiological discrepancies were uncommon but included important cases of false‐negative prediction of PGE dependency and underestimation of obstruction of total anomalous pulmonary venous return. These data can inform more accurate counseling of families with SV‐CHD fetuses and guide diagnostic improvement efforts. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Many approaches to blocking profibrotic TGFβ overexpression are under way. Therapeutic targeting of TGFβ–Smad signaling holds promise for slowing or halting progressive renal disease. In this issue, Fukasawa et al., using the unilateral ureteral obstruction model, provide a new target for therapeutic intervention by identifying loss of the Smad corepressors Ski and SnoN as a mechanism that amplifies the profibrotic actions of TGFβ.Kidney International (2006) 69, 1713–1714. doi:10.1038/sj.ki.5000260 [ABSTRACT FROM AUTHOR]

Objectives: To examine cardiac structural and functional changes in twin-twin transfusion syndrome (TTTS), relative to Quintero stage, as a means of evaluating the spectrum of cardiomyopathy in TTTS. Methods: This was a cross-sectional, retrospective study of 42 consecutive cases of TTTS referred to a single fetal therapy center. Quintero stages were assigned by standard criteria. Presence of ventricular hypertrophy, cardiomegaly, atrioventricular valve regurgitation (AVVR), ventricular systolic dysfunction and right ventricular outflow tract obstruction on fetal echocardiography were noted. The Doppler myocardial performance index (MPI), an index of global ventricular function, was calculated for both ventricles in subjects with adequate Doppler data. We compared cardiac changes across Quintero stages. Results: There was no cardiomyopathy observed in donor twins. The majority of subjects presented at Quintero Stage I (n = 14), II (n = 14) or III (n = 11), with fewer at Stages IV (n = 2) or V (n = 1). As early as Quintero Stages I and II, a significant proportion of recipient twins had ventricular hypertrophy (17/28, 61%), AVVR (6/28, 21%) or quantitative abnormalities in either right (12/24, 50%) or left (14/24, 58%) ventricular function. Increasing prevalence of biventricular systolic dysfunction and cardiomegaly accompanied advancing Quintero stage. Conclusions: Changes in cardiac structure and function not reflected in Quintero staging occur in recipient twins early in the evolution of TTTS. Incorporation of cardiac findings into assessment of TTTS severity may prove useful in stratification of risk and treatment selection. [ABSTRACT FROM AUTHOR]

Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that renin itself might be profibrotic, independent of angiotensin II; however, the signaling system by which renin exerts a direct effect is not known. We tested the hypothesis that renin receptor activation, in turn, activates the extracellular-signal regulated kinase 1 and 2 (ERK1/2) of the mitogen-activated protein kinase system in mesangial cells. Recombinant rat renin induced a rapid phosphorylation of ERK1/2 and subsequent cell proliferation in a dose- and time-dependent manner. ERK1/2 activation by renin addition was not altered by angiotensin-converting enzyme inhibition or angiotensin receptor blockade. An ERK kinase inhibitor significantly reduced the renin-induced ERK1/2 phosphorylation and the subsequent increase in transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 mRNA expression. A small-inhibiting RNA, siRNA, against the renin receptor completely blocked ERK1/2 activation by rat renin. We conclude that renin induces ERK1/2 activation though a receptor-mediated, angiotensin II-independent mechanism in mesangial cells. This renin-activated pathway triggers cell proliferation along with TGF-β1 and plasminogen activator inhibitor-1 gene expression. This system may play an important role in the overall profibrotic actions of renin.Kidney International (2007) 72, 45–52; doi:10.1038/sj.ki.5002243; published online 28 March 2007 [ABSTRACT FROM AUTHOR]

Recent evidence suggesting a strong interplay between components of the renin–angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-β. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-β1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-β1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-β partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-β1. We conclude that renin upregulates MC TGF-β1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-β1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.Kidney International (2006) 69, 105–113. doi:10.1038/sj.ki.5000011 [ABSTRACT FROM AUTHOR]

t-PA promotes glomerular plasmin generation and matrix degradation in experimental glomerulonephritis. Background. In addition to its well-known role in degrading fibrin, recent evidence suggests that plasmin degrades matrix proteins and activates prometalloproteinases. Plasmin is generated from plasminogen by tissue plasminogen activator (t-PA). We hypothesized that t-PA treatment increases plasmin generation in nephritic glomeruli and degrades pathological matrix leading to a therapeutic reduction in matrix accumulation. Methods. Anti–Thy-1 nephritis was induced by injection of OX-7 antibody. Rats were given twice daily intravenous injections of saline (disease control group) or human recombinant t-PA (rt-PA; 1 mg/kg body weight) on days 3 through 5. Proteinuria, glomerular matrix protein staining, and glomerular mRNA levels for transforming growth factor-β1 (TGF-β1), fibronectin, and plasminogen activator inhibitor type 1 (PAI-1) were evaluated at day 6. Localization of rt-PA, plasmin generation by glomeruli in vitro, and glomerular production and content of active TGF-β1 were also investigated. Results. Compared with disease control animals, proteinuria and staining score for periodic acid-Schiff (2.75 ± 0.17 vs. 1.41 ± 0.09), fibronectin-EDA+ (19 ± 2 vs. 14 ± 1), laminin (35 ± 2 vs. 25 ± 2), type I collagen (33 ± 1 vs. 21 ± 3), and type IV collagen (27 ± 2 vs. 23 ± 1) were significantly reduced in treated rats (P < 0.01). Glomerular TGF-β1, fibronectin, and PAI-1 mRNA levels were unchanged. rt-PA colocalized with fibrin along glomerular capillary walls and in the mesangium. Nephritic glomeruli in vitro had decreased plasmin activity, which was elevated by an in vivo presacrifice injection of rt-PA. Glomerular production and content of active TGF-β1 were unchanged by the rt-PA injection. Conclusions. These results show that injected rt-PA binds to fibrin in nephritic glomeruli, thus increasing plasmin generation and promoting pathological matrix degradation without activating latent TGF-β. Agents that increase plasmin generation, such as t-PA, may have potential as antifibrotic therapies. [ABSTRACT FROM AUTHOR]

Many approaches to blocking profibrotic TGFbeta overexpression are under way. Therapeutic targeting of TGFbeta-Smad signaling holds promise for slowing or halting progressive renal disease. In this issue, Fukasawa et al., using the unilateral ureteral obstruction model, provide a new target for therapeutic intervention by identifying loss of the Smad corepressors Ski and SnoN as a mechanism that amplifies the profibrotic actions of TGFbeta. [ABSTRACT FROM AUTHOR]