Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo1

Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo.BackgroundThe fibrinolytic system plays an important role in degrading fibrin-rich thrombi and in vascular and tissue remodeling. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) can reduce the efficiency of the endogenous fibrinolytic system. Angiotensin (Ang) has been shown to regulate PAI-1 expression via the Ang type 1 (AT1) receptor in some tissues and via the AT4 receptor in cultured endothelium. The purpose of this study was to examine the tissue-specific pattern of PAI-1 expression in response to infusion of Ang II in vivo.MethodsAdult male Sprague-Dawley rats (N = 5 in each group) were treated with four hours of intravenous infusions of Ang II or vehicle control while mean arterial pressure (MAP) was monitored: group 1, 600 ng/kg/min Ang II; group 2, Ang II + 10 mg/kg of the AT1 receptor antagonist (AT1RA) L158-809 q2 hour; group 3, Ang II + 0.01 to 0.1 mg/kg hydralazine as required to maintain normal blood pressure; and group 4, saline-infused controls. After infusion, tissue was harvested for Northern blotting, immunohistochemical analysis, and in situ hybridization.ResultsIn group 1, Ang II infusion increased MAP from 105 ± 8 to 160 ± 9 mm Hg (mean ± SE, P < 0.01). Ang II induced increased expression of PAI-1 mRNA in all tissues examined from 5.1-fold in the heart, 9.7-fold in the kidney, 10.0-fold in the aorta, and up to 30.0-fold in the liver (all P < 0.01 vs. control). While both AT1RA (group 3) and hydralazine (group 4) prevented Ang II-induced elevation in blood pressure, the Ang II-dependent expression of PAI-1 mRNA was reduced by only AT1 receptor blockade.ConclusionsWe conclude that in the rat, PAI-1 is induced in a variety of tissues by Ang II directly through the AT1 receptor, independent of its effects on blood pressure

Generation of a core set of items to develop classification criteria for Scleroderma renal crisis using consensus methodology

BACKGROUND This project was undertaken to generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. METHODS An international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In Round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In Round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1-9 (1= very invalid/unfeasible, 5 = uncertain, 9 = very valid/feasible). In Round 3, participants reviewed the results and comments of Round 2, and were asked to provide final ratings. Items rated as highly valid and feasible (both median scores ≥7) in Round 3 were selected as the provisional core set of items. A consensus meeting using nominal group technique (NGT) followed to further reduce the core set of items. RESULTS Ninety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, including hypertension, renal insufficiency, proteinuria and hemolysis. Eleven experts took part in the NGT discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. CONCLUSIONS A core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC. This article is protected by copyright. All rights reserved

Mineralocorticoid Receptor Blocker Protects against Podocyte-Dependent Glomerulosclerosis

Background: We previously showed that angiotensin type 1 receptor (AT1) blocker (ARB) attenuates glomerular injury in Nphs1-hCD25 (NEP25) transgenic mice, a model of selective podocyte injury. However, subsequent studies in NEP25 mice with podocyte-specific deficiency of AT1 revealed that the protective effects of ARB are not through the podocyte AT1, thereby raising the possibility that the protective effects of ARB involve mineralocorticoids. Methods: NEP25 mice were treated with the mineralocorticoid receptor blocker (MRB) spironolactone (25 mg/kg/day, n = 10), the ARB losartan (250 mg/kg/day, n = 11), both (ARB+MRB, n = 8) or vehicle (Vehicle, n = 9) from day –7 to day 9 of induction of podocyte injury. Results: Although MRB did not reduce systolic blood pressure or proteinuria, addition of MRB to ARB significantly attenuated glomerulosclerosis (glomerulosclerosis index: ARB+MRB 1.67 ± 0.19 vs. MRB 2.01 ± 0.29, ARB 2.35 ± 0.19, and Vehicle 2.25 ± 0.26, p Conclusion: These data suggest that, while MRB does not attenuate proteinuria caused by podocyte-specific injury, it provides protective effects against glomerulosclerosis that is independent of systemic blood pressure

CircleSnake: Instance Segmentation with Circle Representation

Circle representation has recently been introduced as a medical imaging optimized representation for more effective instance object detection on ball-shaped medical objects. With its superior performance on instance detection, it is appealing to extend the circle representation to instance medical object segmentation. In this work, we propose CircleSnake, a simple end-to-end circle contour deformation-based segmentation method for ball-shaped medical objects. Compared to the prevalent DeepSnake method, our contribution is three-fold: (1) We replace the complicated bounding box to octagon contour transformation with a computation-free and consistent bounding circle to circle contour adaption for segmenting ball-shaped medical objects; (2) Circle representation has fewer degrees of freedom (DoF=2) as compared with the octagon representation (DoF=8), thus yielding a more robust segmentation performance and better rotation consistency; (3) To the best of our knowledge, the proposed CircleSnake method is the first end-to-end circle representation deep segmentation pipeline method with consistent circle detection, circle contour proposal, and circular convolution. The key innovation is to integrate the circular graph convolution with circle detection into an end-to-end instance segmentation framework, enabled by the proposed simple and consistent circle contour representation. Glomeruli are used to evaluate the performance of the benchmarks. From the results, CircleSnake increases the average precision of glomerular detection from 0.559 to 0.614. The Dice score increased from 0.804 to 0.849. The code has been released: https://github.com/hrlblab/CircleSnakeComment: Machine Learning in Medical Imaging Workshop for 2022 MICCA

Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy

Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy.BackgroundHuman immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by collapsing focal and segmental glomerulosclerosis (FSGS) and microcystic tubular dilatation. HIV-1 infection is also associated with other forms of nephropathy, including mesangial hyperplasia. Since HIV-1 gene products are detected in podocytes and other renal cells, it remains uncertain whether podocyte-restricted HIV-1 gene expression can account for the full spectrum of renal lesions involving nonpodocytes.MethodsTo define the role of podocyte-restricted HIV-1 gene expression in the progression of HIVAN, we generated transgenic mice that express nonstructural HIV-1 genes selectively in podocytes.ResultsFour of the seven founder mice developed proteinuria and nephropathy. In a subsequently established transgenic line, reverse transcription-polymerase chain reaction (RT-PCR) analysis detected mRNAs for vif, vpr, nef, and spliced forms of tat and rev, but not vpu, in the kidney. In situ hybridization localized HIV-1 RNA to the podocyte. Transgenic mice on FVB/N genetic background exhibited cuboidal morphology of podocytes with reduced extension of primary and foot processes at 2 weeks of age. After 3 weeks of age, these mice developed massive and nonselective proteinuria with damage of podocytes and other glomerular cells and, after 4 weeks of age, collapsing FSGS and microcystic tubular dilatation. In marked contrast, transgenic mice with C57BL/6 genetic background showed either normal renal histology or only mild mesangial expansion without overt podocyte damage.ConclusionThe present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background

Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-c

Abstract Background. Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombo

Lymphoma and the Kidney: A Kidney Biopsy Teaching Case

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Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics

Background Hypertensive nephrosclerosis is the presumed underlying cause in many end‐stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. Objective To evaluate and improve the diagnostic process for nephrosclerosis patients. Methods We included adults from the population‐based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988–2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve‐based methods of optimal cut‐offs were used to improve clinical nephrosclerosis criteria. Results Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney‐related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy‐verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false‐positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk‐tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. Conclusion Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.publishedVersio