scholarly journals BK Virus Replication in the Glomerular Vascular Unit: Implications for BK Virus Associated Nephropathy

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 583 ◽  
Author(s):  
Waldemar Popik ◽  
Atanu K. Khatua ◽  
Noyna F. Fabre ◽  
James E. K. Hildreth ◽  
Donald J. Alcendor
Keyword(s):  
Endothelial Cells ◽  
Mesangial Cells ◽  
Graft Loss ◽  
T Antigen ◽  
Bk Virus ◽  
Positive Staining ◽  
Sv40 Large T Antigen ◽  
Qrt Pcr ◽  
Transplant Patients ◽  
Glomerular Endothelial Cells

Background: BK polyomavirus (BKV) reactivates from latency after immunosuppression in renal transplant patients, resulting in BKV-associated nephropathy (BKVAN). BKVAN has emerged as an important cause of graft dysfunction and graft loss among transplant patients. BKV infection in kidney transplant patients has increased over recent decades which correlates with the use of more potent immunosuppressive therapies. BKV infection of the Glomerular Vascular Unit (GVU) consisting of podocytes, mesangial cells, and glomerular endothelial cells could lead to glomerular inflammation and contribute to renal fibrosis. The effects of BKV on GVU infectivity have not been reported. methods: We infected GVU cells with the Dunlop strain of BKV. Viral infectivity was analyzed by microscopy, immunofluorescence, Western blot analysis, and quantitative RT-PCR (qRT-PCR). The expression of specific proinflammatory cytokines induced by BKV was analyzed by qRT-PCR. Results: BKV infection of podocytes, mesangial cells, and glomerular endothelial cells was confirmed by qRT-PCR and positive staining with antibodies to the BKV VP1 major capsid protein, or the SV40 Large T-Antigen. The increased transcriptional expression of interferon gamma-induced protein 10 (CXCL10/IP-10) and interferon beta (IFNβ) was detected in podocytes and mesangial cells at 96 h post-infection. conclusions: All cellular components of the GVU are permissive for BKV replication. Cytopathic effects induced by BKV in podocytes and glomerular endothelial cells and the expression of CXCL10 and IFNβ genes by podocytes and mesangial cells may together contribute to glomerular inflammation and cytopathology in BKVAN.

scholarly journals BK Virus RNA in Renal Allograft Biopsies

2020 ◽  
Vol 68 (5) ◽  
pp. 319-325 ◽  
Author(s):  
Francesca Costigliolo ◽  
Kara Lombardo ◽  
Lois J. Arend ◽  
Avi Z. Rosenberg ◽  
Andres Matoso ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Jc Virus ◽  
Graft Loss ◽  
T Antigen ◽  
Bk Virus ◽  
Kidney Transplant Recipients ◽  
Sv40 Large T Antigen ◽  
Virus Rna ◽  
Allograft Biopsy ◽  
Alternative Test

BK polyomavirus–associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC ( R2 = 0.65, p<0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.

Abstract P016: GYY4137, a Hydrogen Sulfide Donor, Mitigates Ang II-induced Extracellular Matrix Remodeling in Glomerular Endothelial and Mesangial Cells

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Matthew Amin ◽  
Sathnur Pushpakumar ◽  
Sourav Kundu ◽  
Geetansh Tyagi ◽  
Aaron Tyagi ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Hydrogen Sulfide ◽  
Mesangial Cells ◽  
Collagen Iv ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Remodeling ◽  
Ang Ii ◽  
Hypertensive Nephropathy ◽  
Glomerular Endothelial Cells

Hypertensive nephropathy is associated with progressive alteration of extracellular matrix (ECM) components. Both mesangial and glomerular endothelial cells have the ability to synthesize and degrade ECM proteins such as collagens by changes in the activity of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Endo180 is an extracellular fibronectin type II domain involved in lysosomal degradation of collagen which has been shown to mitigate renal fibrosis. More recently, hydrogen sulfide (H2S) has also been shown to mitigate hypertensive renal remodeling, however, its mechanism remains unclear. In this study, our aim was to investigate whether Angiotensin-II (Ang II) treatment alters the expression of Endo180, MMPs and TIMPs leading to dysregulation of collagen metabolism and whether GYY4137 (H2S donor) restores their levels to achieve homeostasis. Mesangial and mouse glomerular endothelial cells (MCs and MGECs respectively) were treated without or with Ang II (200 nM) and GYY4137 (250 μM) for 48hrs. Cell lysates were analyzed for MMP-13, -14, TIMP-1, Endo180, and collagen IV by Western blot, RT-PCR, and immunohistochemistry. In MGECs, Ang II treatment compared to its control decreased MMP-13/TIMP-1 ratio (0.75±0.44 vs. 2.48 ±0.73), and upregulated MMP-14/TIMP-1 ratio (0.64±2.10 vs. 0.96±1.47), and collagen IV (0.77±0.07 vs. 0.58±0.06). GYY4137 treatment mitigated these changes. In contrast, Ang II treatment in MCs decreased Endo180 compared to control (0.72±0.04 vs. 1.07±0.23), but did not alter the expression of MMP-13/TIMP-1, MMP-14/TIMP-1 ratios, and collagen IV level compared to control or MGECs. Similarly, immunostaining showed downregulation of MMP-13 and Endo180 in Ang II treated MGECs which was normalized following GYY4137 treatment. Endo180 was also normalized in MCs following GYY4137 treatment however, there was no change in MMP-14/TIMP-1 ratio or collagen IV level. We conclude that Ang II treatment causes adverse ECM remodeling in MGECs via downregulation of Endo180 and MMP-13 and upregulation of MMP-14 and TIMP-1 and in MCs by decreasing Endo180, and GYY4137 mitigates these changes in part, by modulating Endo180/MMP/TIMP pathway.

Glomerular endothelial cells respond to calcium-mobilizing agonists with release of EDRF

1990 ◽  
Vol 258 (5) ◽  
pp. F1295-F1303 ◽  
Author(s):  
P. A. Marsden ◽  
T. A. Brock ◽  
B. J. Ballermann
Keyword(s):  
Endothelial Cells ◽  
Calcium Concentration ◽  
Mesangial Cells ◽  
Platelet Activating Factor ◽  
Cytosolic Calcium ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Concentration Dependent Manner ◽  
Glomerular Function ◽  
Glomerular Endothelial Cells

To determine whether glomerular endothelial cells (GEN) may play a role in the local control of glomerular function by releasing endothelium-derived relaxing factor (EDRF), the effect of several agonists on GEN cytosolic calcium concentration ([Ca2+]i) and GEN EDRF release was determined. Bradykinin, ATP, thrombin, and platelet-activating factor (PAF) all increased [Ca2+]i in GEN in a concentration-dependent manner, whereas serotonin, acetylcholine, phenylephrine, and endothelin-1 were without effect. Coincubation of glomerular mesangial cells (GMC) with GEN augmented mesangial cell guanosine 3',5'-cyclic monophosphate (cGMP) content five- to sixfold, Bradykinin elicited a further concentration-dependent increase in GMC cGMP content in the presence but not absence of GEN. The GEN-dependent bradykinin-stimulated GMC cGMP accumulation was abolished by hemoglobin and methylene blue, blunted by gossypol, and augmented by superoxide dismutase. Other agonists capable of augmenting GEN [Ca2+]i also stimulated GMC cGMP accumulation in the presence but not in the absence of GEN. Thus cultured GEN release a factor that stimulates cGMP accumulation in adjacent mesangial cells which has the pharmacological characteristics of EDRF.

scholarly journals Development of Glomerular Endothelial Cells, Podocytes and Mesangial Cells in the Human Fetus and Infant

2007 ◽  
Vol 212 (1) ◽  
pp. 81-90 ◽  
Author(s):  
Kei Takano ◽  
Yukihiko Kawasaki ◽  
Tomoko Imaizumi ◽  
Hiromi Matsuura ◽  
Ruriko Nozawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Fetus ◽  
Mesangial Cells ◽  
Glomerular Endothelial Cells

scholarly journals Glomerular endothelial cells synthesize collagens but little gelatinase A and B.

1998 ◽  
Vol 9 (11) ◽  
pp. 2040-2047
Author(s):  
O Lenz ◽  
L J Striker ◽  
T A Jacot ◽  
S J Elliot ◽  
P D Killen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Mesangial Cells ◽  
Matrix Metalloproteinase 2 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Mrna Levels ◽  
Glomerular Cell ◽  
Glomerular Endothelial Cells ◽  
Extracellular Matrix Components

Mesangial sclerosis is a major feature of progressive renal disease. The mesangium contains mesangial cells and is bounded by the peripheral glomerular basement membrane and endothelial cells. Mesangial cells synthesize and degrade extracellular matrix. Whereas both mesangial and endothelial cells synthesize extracellular matrix components, the degradative pathway, well studied in the former, has not been investigated in endothelial cells. This study examines lines of all three glomerular cell types derived from female B6SJLF1/J mice, as well as mRNA levels for collagens alpha1(I), alpha1(IV), alpha3 (IV), alpha5 (IV), and alpha1 (VI), laminin, tenascin, matrix metalloproteinase-2 (MMP-2), and MMP-9. Type I and IV collagen synthesis was confirmed by enzyme-linked immunosorbent assay. MMP-2 and MMP-9 enzyme activity was measured by zymography. It was found that glomerular endothelial cells are a significant source of collagens, laminin, and tenascin. However, they express only low levels of MMP-2 and no detectable MMP-9. Stimulation with exogenous transforming growth factor-beta1 leads to a significant increase in collagen I, tissue inhibitors of metalloproteinase-1, and MMP-9 in conditioned media. These data suggest that glomerular endothelial cells may play an active role in extracellular matrix remodeling in glomerular disease.

scholarly journals Activities of Different Classes of Acyclic Nucleoside Phosphonates against BK Virus in Primary Human Renal Cells

2011 ◽  
Vol 55 (5) ◽  
pp. 1961-1967 ◽  
Author(s):  
D. Topalis ◽  
I. Lebeau ◽  
M. Krečmerová ◽  
G. Andrei ◽  
R. Snoeck
Keyword(s):  
Graft Loss ◽  
Bk Virus ◽  
Virus Infections ◽  
Renal Cells ◽  
Dna Virus ◽  
Transplant Patients ◽  
Proximal Tubular Epithelial Cells ◽  
Acyclic Nucleoside Phosphonates ◽  
Acyclic Nucleoside ◽  
Renal Proximal Tubular

ABSTRACTBK virus (BKV), a virus belonging to the polyomavirus family, is a circular double-stranded DNA virus that causes nephropathies in immunocompromised patients after kidney or bone marrow transplantation. The occurrence of polyomavirus-associated nephropathy in kidney transplant patients may trigger graft loss, and guidelines for the management of BKV infection have not yet been clearly established. Treatment of BKV nephropathy with cidofovir (CDV) {(S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC)}, an acyclic phosphonate analogue of dCMP with a broad antiviral activity against DNA virus infections, has been proposed. The benefit of this small-molecule-based treatment has been evaluated only with a limited number of cases. In this study, we report the evaluation of three different classes of acyclic nucleoside phosphonates for their activities against BKV replication in two different primary renal cells: renal proximal tubular epithelial cells (RPTECs) and human renal cortical epithelial (HRCE) cells. The data indicate that besides HPMPC and its cyclic form, (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), cyclic HPMP (cHPMP)-5-azaC, hexadecyloxyethyl (HDE)-cHPMP-5-azaC, and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) are the most selective inhibitors of BKV replication. On the contrary, leflunomide, which has also been proposed for the management of BKV-associated diseases, is not able to inhibit BKV replication at nontoxic concentrations.

scholarly journals Endothelin A Receptors Expressed in Glomeruli of Renal Transplant Patients May Be Associated with Antibody-Mediated Rejection

2021 ◽  
Vol 10 (3) ◽  
pp. 422
Author(s):  
Katarzyna Nowańska ◽  
Mirosław Banasik ◽  
Piotr Donizy ◽  
Katarzyna Kościelska-Kasprzak ◽  
Sławomir Zmonarski ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Graft Loss ◽  
Human Leukocyte ◽  
Positive Staining ◽  
Antibody Mediated Rejection ◽  
Transplant Patients ◽  
Endothelin A Receptor ◽  
Microscopic Evaluation ◽  
Eta Receptor ◽  
Endothelin A

Background: Non-human leukocyte antigen (HLA) anti-endothelin A receptor antibodies are presented as being potentially important, but the expression of the endothelin A receptor in glomeruli (ETA receptor (g+)) has not yet been described. We decided to evaluate the presence and relevance of the ETA receptor in for-cause renal transplant biopsies. The aim of our study was to evaluate the immunoreactivity of the ETA receptor and its significance in patients who underwent a renal transplant biopsy due to the deterioration of transplant function, with detailed characterization of staining in glomeruli. Methods: The immunohistochemical expression of ETA receptor (ETAR) was analyzed in renal transplant biopsies. Microscopic evaluation was performed on paraffin sections in glomeruli. The analysis was performed using a two-step scale (0: lack of ETAR expression; 1: the presence of ETAR expression—mild to moderate immunoreactivity). Results: We analyzed 149 patients who underwent renal allograft biopsy after renal transplantation. Positive staining of ETA receptors in glomeruli (ETA receptor (g+)) was noticed in 13/149 (8.7%) patients. Five of these 13 (38.5%) patients with ETA receptor (g+) developed antibody-mediated rejection (AMR), while 13 of the remaining 136 (9.5%) ETA receptor (g-) patients developed AMR (p = 0.0022). Graft loss was noticed in all but one ETA receptor (g+) patient with AMR (4/5; 80%), but only in 2/13 (15%) ETA receptor (g-) patients with AMR (p = 0.009) during the first year after biopsy. Conclusions: The expression of endothelin A receptors in glomeruli seems to be a potentially important feature in the diagnosis of damage during antibody-mediated rejection. It may help to identify patients at a higher risk of allograft rejection and injury.

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