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           Search results for: Human Glomerular Microvascular Endothelial Cells   

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Utilizing a Kidney-Targeting Peptide to Improve Renal Deposition of a Pro-Angiogenic Protein Biopolymer.

Elastin-like polypeptides (ELP) are versatile protein biopolymers used in drug delivery due to their modular nature, allowing fusion of therapeutics and targeting agents. We previously developed an ELP fusion with vascular endothelial growth factor (VEGF) and demonstrated its therapeutic efficacy in translational swine models of renovascular disease and chronic kidney disease. The goal of the current work was to refine renal targeting and reduce off-target tissue deposition of ELP-VEGF. The ELP-VEGF fusion protein was modified by adding a kidney-targeting peptide (KTP) to the N-terminus. All control proteins (ELP, KTP-ELP, ELP-VEGF, and KTP-ELP-VEGF) were also produced to thoroughly assess the effects of each domain on in vitro cell binding and activity and in vivo pharmacokinetics and biodistribution. KTP-ELP-VEGF was equipotent to ELP-VEGF and free VEGF in vitro in the stimulation of primary glomerular microvascular endothelial cell proliferation, tube formation, and extracellular matrix invasion. The contribution of each region of the KTP-ELP-VEGF protein to the cell binding specificity was assayed in primary human renal endothelial cells, tubular epithelial cells, and podocytes, demonstrating that the VEGF domain induced binding to endothelial cells and the KTP domain increased binding to all renal cell types. The pharmacokinetics and biodistribution of KTP-ELP-VEGF and all control proteins were determined in SKH-1 Elite hairless mice. The addition of KTP to ELP slowed its in vivo clearance and increased its renal deposition. Furthermore, addition of KTP redirected ELP-VEGF, which was found at high levels in the liver, to the kidney. Intrarenal histology showed similar distribution of all proteins, with high levels in blood vessels and tubules. The VEGF-containing proteins also accumulated in punctate foci in the glomeruli. These studies provide a thorough characterization of the effects of a kidney-targeting peptide and an active cytokine on the biodistribution of these novel biologics. Furthermore, they demonstrate that renal specificity of a proven therapeutic can be improved using a targeting peptide.

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Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature.

Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3β phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.

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Human Vascular Pericytes and Cytomegalovirus Pathobiology.

Pericytes are multipotent cells of the vascular system with cytoplasmic extensions proximal to endothelial cells that occur along the abluminal surface of the endothelium. The interactions between endothelial cells and pericytes are essential for proper microvascular formation, development, stabilization, and maintenance. Pericytes are essential for the regulation of paracellular flow between cells, transendothelial fluid transport, angiogenesis, and vascular immunosurveillance. They also influence the chemical composition of the surrounding microenvironment to protect endothelial cells from potential harm. Dysregulation or loss of pericyte function can result in microvascular instability and pathological consequences. Human pericytes have been shown to be targets for human cytomegalovirus (HCMV) infection and lytic replication that likely contribute to vascular inflammation. This review focuses on human vascular pericytes and their permissiveness for HCMV infection. It also discusses their implication in pathogenesis in the blood⁻brain barrier (BBB), the inner blood⁻retinal barrier (IBRB), the placenta⁻blood barrier, and the renal glomerulus as well as their potential role in subclinical vascular disease.

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Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens.

Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.

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Sphingosine-1-phosphate promotes barrier-stabilizing effects in human microvascular endothelial cells via AMPK-dependent mechanisms.

Breakdown of the endothelial barrier is a critical step in the development of organ failure in severe inflammatory conditions such as sepsis. Endothelial cells from different tissues show phenotypic variations which are often neglected in endothelial research. Sphingosine-1-phosphate (S1P) and AMP-dependent kinase (AMPK) have been shown to protect the endothelium and phosphorylation of AMPK by S1P was shown in several cell types. However, the role of the S1P-AMPK interrelationship for endothelial barrier stabilization has not been investigated. To assess the role of the S1P-AMPK signalling axis in this context, we established an in vitro model allowing real-time monitoring of endothelial barrier function in human microvascular endothelial cells (HMEC-1) and murine glomerular endothelial cells (GENCs) with the electric cell-substrate impedance sensing (ECIS™) system. Following the disruption of the cell barrier by co-administration of LPS, TNF-α, IL-1ß, IFN-γ, and IL-6, we demonstrated self-recovery of the disrupted barrier in HMEC-1, while the barrier remained compromised in GENCs. Under physiological conditions we observed a rapid phosphorylation of AMPK in HMEC-1 stimulated with S1P, but not in GENCs. Consistently, S1P enhanced the basal endothelial barrier in HMEC-1 exclusively. siRNA-mediated knockdown of AMPK in HMEC-1 led to a less pronounced barrier enhancement. Thus we present evidence for a functional role of AMPK in S1P-mediated barrier stabilization in HMEC-1 and we provide insight into cell-type specific differences of the S1P-AMPK-interrelationship, which might influence the development of interventional strategies targeting endothelial barrier dysfunction.

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Heme Drives Susceptibility of Glomerular Endothelium to Complement Overactivation Due to Inefficient Upregulation of Heme Oxygenase-1.

Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in and models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, and , compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4-known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

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Endothelium structure and function in kidney health and disease.

The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.

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Protein kinase C and protein kinase A are involved in the protection of recombinant human glucagon-like peptide-1 on glomeruli and tubules in diabetic rats.

Blockade or reversal the progression of diabetic nephropathy is a clinical challenge. The aim of the present study was to examine whether recombinant human glucagon-like peptide-1 (rhGLP-1) has an effect on alleviating urinary protein and urinary albumin levels in diabetic rats.

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Shiga toxin-glycosphingolipid interaction: Status quo of research with focus on primary human brain and kidney endothelial cells.

Shiga toxin (Stx)-mediated injury of the kidneys and the brain represent the major extraintestinal complications in humans upon infection by enterohemorrhagic Escherichia coli (EHEC). Damage of renal and cerebral endothelial cells is the key event in the pathogenesis of the life-threatening hemolytic uremic syndrome (HUS). Stxs are AB toxins and the B-pentamers of the two clinically important Stx subtypes Stx1a and Stx2a preferentially bind to the glycosphingolipid globotriaosylceramide (Gb3Cer, Galα4Galβ4Glcβ1Cer) and to less extent to globotetraosylceramide (Gb4Cer, GalNAcβ3Galα4Galβ4Glcβ1), which are expected to reside in lipid rafts in the plasma membrane of the human endothelium. This review summarizes the current knowledge on the Stx glycosphingolipid receptors and their lipid membrane ensemble in primary human brain microvascular endothelial cells (pHBMECs) and primary human renal glomerular endothelial cells (pHRGECs). Increasing knowledge on the precise initial molecular mechanisms by which Stxs interact with cellular targets will help to develop specific therapeutics and/or preventive measures to combat EHEC-caused diseases.

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Low-intensity pulsed ultrasound in combination with SonoVue induces cytotoxicity of human renal glomerular endothelial cells via repression of the ERK1/2 signaling pathway.

Low-intensity pulsed ultrasound (LIPUS) and SonoVue have been used widely for diagnosis and therapeutic treatment. The effects of LIPUS and SonoVue on the microvascular system and underlying molecular mechanisms have not been established.

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