Enhanced activation of interleukin-10, heme oxygenase-1, and AKT in C5aR2-deficient mice is associated with protection from ischemia reperfusion injury-induced inflammation and fibrosis.

Severe ischemia reperfusion injury (IRI) results in rapid complement activation, acute kidney injury and progressive renal fibrosis. Little is known about the roles of the C5aR1 and C5aR2 complement receptors in IRI. In this study C5aR1-/- and C5aR2-/- mice were compared to the wild type in a renal IRI model leading to renal fibrosis.

Renal ischemia-reperfusion injury causes hypertension and renal perfusion impairment in the CD1 mice which promotes progressive renal fibrosis.

Renal ischemia-reperfusion injury (IRI) is a severe complication of major surgery and a risk factor for increased morbidity and mortality. Here, we investigated mechanisms that might contribute to IRI-induced progression to chronic kidney disease (CKD). Acute kidney injury (AKI) was induced by unilateral IRI for 35 min in CD1 and C57BL/6 (B6) mice.

IL-17A blockade or deficiency does not affect progressive renal fibrosis following renal ischaemia reperfusion injury in mice.

Objectives: IL-17A contributes to acute kidney injury and fibrosis. Therefore, we asked whether IL-17A deficiency or treatment with a IL-17A blocking antibody impacts severe renal ischaemia reperfusion injury (IRI) and the progression to chronic kidney disease (CKD).

Methods: IL-17A-deficient and wild-type (WT) mice underwent transient unilateral renal pedicle clamping for 45 min to induce IRI and subsequent renal fibrosis.

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV).

Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis.

Objective: Angiopoietin-2, a protein secreted by stimulated endothelium and an antagonist of the endothelium-stabilizing receptor Tie2, contributes to the pathophysiology of septic multiple organ dysfunction. We tested the therapeutic potential of a pulmonary-endothelium-specific RNA interference-based angiopoietin-2 targeting strategy in sepsis.

Design: Laboratory and animal research.

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI.

Knockdown of the hypertension-associated gene NOSTRIN alters glomerular barrier function in zebrafish (Danio rerio).

Hypertension is one of the major risk factors for chronic kidney disease. Using quantitative trait loci analysis, we identified the gene of the F-BAR protein NOSTRIN in the center of an overlapping region in rat and human quantitative trait loci that are associated with hypertension. Immunohistochemical analysis revealed a predominantly podocytic expression pattern of NOSTRIN in human and mouse glomeruli.

Aldosterone modulates endothelial permeability and endothelial nitric oxide synthase activity by rearrangement of the actin cytoskeleton.

Aldosterone (Aldo) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Aldo alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells were exposed to Aldo (10(-9) mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions and activation of intracellular signaling pathways were determined.

Dehydroepiandrosterone-induced phosphorylation and translocation of FoxO1 depend on the mineralocorticoid receptor.

In humans, dehydroepiandrosterone (DHEA), with its sulfate, is the most abundant adrenal steroid, whereas the rat adrenals are not capable of synthesizing this steroid. Circulating concentrations of DHEA sulfate lie in the millimolar range and those of DHEA in the subnanomolar range. DHEA exerts protective potential during vascular remodeling, although the underlying mechanisms of this protection are imperfectly defined.

The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.

CD4+ T cells contribute to the pathogenesis of ischemia-reperfusion injury, which is the primary cause of delayed graft failure after kidney transplantation. The TIM-1:TIM-4 pathway participates in the activation/differentiation of CD4+ T cells, suggesting that it may modulate ischemia-reperfusion injury. Here, we studied the role of TIM-1 in a murine uninephrectomized renal ischemia-reperfusion injury model.

Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing.

The clinical importance of microparticles resulting from vesiculation of platelets and other blood cells is increasingly recognized, although no standardized method exists for their measurement. Only a few studies have examined the analytical and preanalytical steps and variables affecting microparticle detection. We focused our analysis on microparticle detection by flow cytometry.

Urinary excretion of twenty peptides forms an early and accurate diagnostic pattern of acute kidney injury.

Early and accurate detection of acute kidney injury (AKI) is needed to prevent the progression to chronic kidney disease and to improve outcome. Here we used capillary electrophoresis-mass spectrometry to identify urinary peptides predictive of AKI in a training set of 87 urine samples longitudinally collected from patients in an intensive care unit. Within this patient cohort, 16 developed AKI while 14 maintained normal renal function.

Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells.

Background: Endothelial tight and adherens junctions control a variety of physiological processes like adhesion, paracellular transport of solutes or trafficking of activated leukocytes. Formation and maintenance of endothelial junctions largely depend on the microenvironment of the specific vascular bed and on interactions of the endothelium with adjacent cell types. Consequently, primary cultures of endothelial cells often lose their specific junctional pattern and fail to establish tight monolayer in vitro.

Growth arrest specific protein 6 participates in DOCA-induced target-organ damage.

Growth arrest-specific protein 6 (Gas 6) is involved in inflammatory kidney diseases, vascular remodeling, cell adhesion, and thrombus formation. We explored a role for Gas 6 in aldosterone-induced target organ damage. We observed that Gas 6 was upregulated in rats with high aldosterone levels.

Endothelial-derived thrombospondin-1 promotes macrophage recruitment and apoptotic cell clearance.

Rapid apoptotic cell engulfment is crucial for prevention of inflammation and autoimmune diseases and is conducted by special immunocompetent cells like macrophages or immature dendritic cells. We recently demonstrated that endothelial cells (ECs) also participate in apoptotic cell clearance. However, in contrast to conventional phagocytes they respond with an inflammatory phenotype.

Transcriptome changes in renal allograft protocol biopsies at 3 months precede the onset of interstitial fibrosis/tubular atrophy (IF/TA) at 6 months.

Background: Interstitial fibrosis and tubular atrophy (IF/TA) in renal transplants are the major morphological correlates of progressive graft deterioration. Early diagnosis of IF/TA is a pre-requisite for a timely therapeutic intervention in patients at risk. To evaluate events occurring before the overt onset of IF/TA, gene expression profiling of 3-month protocol biopsies from patients with IF/TA was performed in a patient group (n = 8) who developed mild IF/TA [chronic allograft nephropathy (CAN) grade I, by the Banff scoring system] in the subsequent 6-month protocol biopsy ('progressors'), and in 12 patients without IF/TA at 6 months ('non-progressors').

Renal urokinase-type plasminogen activator (uPA) receptor but not uPA deficiency strongly attenuates ischemia reperfusion injury and acute kidney allograft rejection.

Central mechanisms leading to ischemia induced allograft rejection are apoptosis and inflammation, processes highly regulated by the urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR). Recently, up-regulation of uPA and uPAR has been shown to correlate with allograft rejection in human biopsies. However, the causal connection of uPA/uPAR in mediating transplant rejection and underlying molecular mechanisms remain poorly understood.

Glucocorticoid-related signaling effects in vascular smooth muscle cells.

Mineralocorticoid receptor blockade protects from angiotensin II-induced target-organ damage. 11beta-Hydroxysteroid dehydrogenase type 2 protects the mineralocorticoid receptor from activation by glucocorticoids; however, high glucocorticoid concentrations and absent 11beta-hydroxysteroid dehydrogenase type 2 in some tissues make glucocorticoids highly relevant mineralocorticoid receptor ligands. We investigated the effects of corticosterone (10(-6) to 10(-12) mol/L) on early vascular mineralocorticoid receptor signaling by Western blotting, confocal microscopy, and myography.

Circulating endothelial cells: a marker of vascular damage in patients with preeclampsia.

Objective: Preeclampsia is a disorder of endothelial cells, and novel markers of the disease are eagerly awaited. We tested the hypothesis that circulating endothelial cells (CECs) are elevated in preeclampsia and that cell numbers correlate with disease activity.

Study Design: CECs were measured in 10 patients with preeclampsia as well as pregnant and nonpregnant controls.

Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages.

Statins induce heme oxygenase-1 (HO-1) in several cell types, such as vascular smooth muscle cells, endothelial cells, and macrophages. The present study assessed the role of statin-induced HO-1 up-regulation on circulating monocytes/macrophages and their contribution in preventing renal ischemia-reperfusion (IR) injury in a rat model. Cerivastatin was administered via gavage (0.

Deletion of protein kinase C-beta isoform in vivo reduces renal hypertrophy but not albuminuria in the streptozotocin-induced diabetic mouse model.

The protein kinase C (PKC)-beta isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-beta-deficient (PKC-beta(-/-)) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-beta(-/-) mice compared with appropriate 129/SV wild-type mice.

Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses.

Circulating endothelial cells (CECs) have been detected in a variety of vascular disorders, but their interactions with healthy endothelium remain unknown. The aim of this study was to evaluate the response of human endothelial cells (ECs) to apoptotic or necrotic ECs in an in vitro model and to delineate pathogenetic pathways. Here we show that incubation of the human microvascular endothelial cell line (HMEC-1) with apoptotic ECs resulted in increased expression of chemokines and enhanced binding of leukocytes to HMEC-1 cells, whereas exposure of HMEC-1 cells to necrotic ECs caused no changes in leukocyte-binding affinity.

Circulating endothelial cells as a prognostic marker in thrombotic microangiopathy.

Background: Circulating endothelial cells (CECs) are a reliable marker of disease activity in a variety of vascular disorders. Damage to microvascular endothelial cells is a hallmark of thrombotic microangiopathy (TMA). The aim of this study is to identify and count CECs during the course of TMA and evaluate whether cell numbers may serve as a prognostic marker in patients undergoing plasma exchange.