scholarly journals A ROLE OF POLYMORPHONUCLEAR LEUKOCYTES AND COMPLEMENT IN NEPHROTOXIC NEPHRITIS

1965 ◽  
Vol 122 (1) ◽  
pp. 99-116 ◽  
Author(s):  
Charles G. Cochrane ◽  
Emil R. Unanue ◽  
Frank J. Dixon
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Basement Membranes ◽  
Ultrastructural Changes ◽  
Glomerular Injury ◽  
Large Numbers ◽  
Secondary Stage ◽  
Vascular Beds ◽  
Nephrotoxic Nephritis ◽  
Glomerular Damage

In acute nephrotoxic nephritis, polymorphonuclear leukocytes (polymorphs) accumulated in large numbers in the glomeruli in the first 12 hours. The endothelial cells were dislodged by the polymorphs which then came to lie immediately adjacent to the glomerular basement membranes. Ultrastructural changes in neither polymorphs nor basement membranes were observed. Depletion of polymorphs in both rats and rabbits prevented the development of proteinuria. This occurred when doses of nephrotoxic globulin were employed that produced proteinurias of as much as 1800 mg/kg/24 hours in intact rabbits, or enough to yield near maximal immediate proteinuria in intact rats. In addition, measurable glomerular damage was frequently averted until the onset of the secondary stage of NTN. Controls indicated that the polymorph depleted animals exhibited minimal non-specific changes in the blood, that the ability of their vascular beds to react to stimuli was not affected, and that deposition of nephrotoxic antibody and C' in the glomeruli was not inhibited. Elimination of polymorphs from the circulation was only partially effective in preventing glomerular damage when large doses of nephrotoxic globulin were used. This indicated that under these circumstances, a polymorph independent glomerular injury may also take place in first stage nephrotoxic nephritis. An indirect role of C', i.e., the accumulation of polymorphs, in bringing about glomerular injury in first stage nephrotoxic nephritis was apparent. When rabbit nephrotoxic globulin was injected into rats depleted of C', or when duck nephrotoxic globulin that fixed C' poorly was injected into normal rats, C' failed to bind with the antibody along glomerular basement membranes and polymorphs did not accumulate.

scholarly journals Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

1997 ◽  
Vol 8 (11) ◽  
pp. 1712-1721 ◽  
Author(s):  
V Bremer ◽  
A Tojo ◽  
K Kimura ◽  
Y Hirata ◽  
A Goto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Early Stage ◽  
Renal Tissue ◽  
Macrophage Infiltration ◽  
Intercellular Adhesion Molecule ◽  
No Production ◽  
Sprague Dawley ◽  
Nephrotoxic Nephritis ◽  
Glomerular Damage

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

scholarly journals A rat model of progressive chronic glomerular sclerosis: the role of thromboxane inhibition.

1992 ◽  
Vol 2 (11) ◽  
pp. 1568-1577
Author(s):  
R A Stahl ◽  
F Thaiss ◽  
U Wenzel ◽  
W Schoeppe ◽  
U Helmchen
Keyword(s):  
Rat Model ◽  
Mesangial Cells ◽  
Combined Treatment ◽  
Damage Index ◽  
Glomerular Sclerosis ◽  
Interventional Treatment ◽  
Glomerular Injury ◽  
Glomerular Lesion ◽  
Glomerular Damage

In order to evaluate a possible role of thromboxane A2 (TxA2) in the pathophysiology of chronic glomerular disease, we studied the effect of a 12-wk combined treatment with the thromboxane receptor blocker Daltroban (D) and the thromboxane synthesis inhibitor UK 38485 (UK) on glomerular function and morphology in a rat model of chronic progressive glomerular injury. The glomerular lesion was induced in unilaterally nephrectomized rats by the repeated i.v. injection of an antibody directed against mesangial cells. Control rats were uninephrectomized. Three months after the first antibody injection before D and UK treatment, albuminuria (35.8 +/- 3.6 mg/24 h) and glomerular TxB2 formation (146 +/- 20 pg/mg of protein/min) were significantly higher compared with control values (albuminuria, 14.3 +/- 3.5 mg/24 h; TxB2, 59 +/- 16 pg/mg/min). Six months after antibody, albuminuria in nephritic rats had increased to 135 +/- 17 mg/24 h. In nephritic rats treated with D plus UK, albuminuria (44 +/- 12 mg/24 h), however, was significantly (P less than 0.001) inhibited. Quantitative morphological analysis (glomerular damage index) 6 months after antibody revealed significantly (P less than 0.001) increased glomerular lesions in nephritic rats (0.353 +/- 0.095) compared with that in uninephrectomized controls (0.045 +/- 0.014). The treatment of rats with D and UK significantly (P less than 0.001) reduced the glomerular damage index (0.101 +/- 0.004) in nephritic rats. D plus UK treatment reduced glomerular TxB2 formation but increased prostaglandin E2 and 6-keto prostaglandin F1 alpha release by isolated glomeruli. This study demonstrates that interventional treatment with D and UK ameliorates albuminuria and glomerular morphological lesions in a rat model of immunologically induced progressive glomerular injury.

scholarly journals Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy

2020 ◽  
Vol 31 (9) ◽  
pp. 2013-2024 ◽  
Author(s):  
Akiko Takahata ◽  
Satoko Arai ◽  
Emiri Hiramoto ◽  
Kento Kitada ◽  
Rina Kato ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Leukocyte Infiltration ◽  
Wild Type ◽  
Glomerular Injury ◽  
Glomerular Lesions ◽  
Apoptosis Inhibitor ◽  
Immune Complex Formation ◽  
Glomerular Damage ◽  
Apoptosis Inhibitor Of Macrophage

BackgroundIgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages’ function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.MethodsWe established an AIM-deficient IgAN model (AIM−/−gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA−/−gddY) was also generated to further determine the role of AIM.ResultsIn both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM−/−gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA−/−gddY mice.ConclusionsAIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.

scholarly journals Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice

2021 ◽  
Vol 14 (9) ◽  
Author(s):  
Bernhard N. Bohnert ◽  
Irene Gonzalez-Menendez ◽  
Thomas Dörffel ◽  
Jonas C. Schneider ◽  
Mengyun Xiao ◽  
...  
Keyword(s):  
Essential Role ◽  
Mendelian Inheritance ◽  
Glomerular Injury ◽  
Nucleotide Polymorphism ◽  
Repair Enzyme ◽  
Gene Encoding ◽  
Single Nucleotide ◽  
Genetic Deficiency ◽  
Glomerular Damage

ABSTRACT Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria in mice, is related to the single-nucleotide polymorphism (SNP) C6418T of the Prkdc gene encoding for the DNA-repair enzyme DNA-PKcs. In addition, plasminogen (Plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the Prkdc gene in C57BL/6 (PrkdcC6418/C6418) and 129S1/SvImJ (PrkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with PrkdcT6418/T6418 developed proteinuria. Genetic deficiency of Plg (Plg−/−) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of Plg in Plg+/+ mice after doxorubicin injection involving histone H2B as Plg receptor. In doxorubicin-resistant C57BL/6 mice, Plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two-hit process requiring the C6418T SNP in the Prkdc gene and subsequent glomerular binding of Plg. This article has an associated First Person interview with the first author of the paper.

scholarly journals Essential role of Gas6 for glomerular injury in nephrotoxic nephritis

2002 ◽  
Vol 110 (2) ◽  
pp. 239-246 ◽  
Author(s):  
Motoko Yanagita ◽  
Yoshikazu Ishimoto ◽  
Hidenori Arai ◽  
Kojiro Nagai ◽  
Tsuyoshi Ito ◽  
...  
Keyword(s):  
Essential Role ◽  
Glomerular Injury ◽  
Nephrotoxic Nephritis

scholarly journals The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2464
Author(s):  
Nicole Mangold ◽  
Jeffrey Pippin ◽  
David Unnersjoe-Jess ◽  
Sybille Koehler ◽  
Stuart Shankland ◽  
...  
Keyword(s):  
Glomerular Disease ◽  
Cyclin Dependent Kinase ◽  
Developmental Defects ◽  
Differentiated Cells ◽  
Glomerular Epithelial Cells ◽  
Glomerular Development ◽  
Nephrotoxic Nephritis ◽  
Cyclin Dependent Kinase 5 ◽  
Glomerular Damage

Cyclin-dependent kinase 5 (Cdk5) is expressed in terminally differentiated cells, where it drives development, morphogenesis, and survival. Temporal and spatial kinase activity is regulated by specific activators of Cdk5, dependent on the cell type and environmental factors. In the kidney, Cdk5 is exclusively expressed in terminally differentiated glomerular epithelial cells called podocytes. In glomerular disease, signaling mechanisms via Cdk5 have been addressed by single or combined conventional knockout of known specific activators of Cdk5. A protective, anti-apoptotic role has been ascribed to Cdk5 but not a developmental phenotype, as in terminally differentiated neurons. The effector kinase itself has never been addressed in animal models of glomerular disease. In the present study, conditional and inducible knockout models of Cdk5 were analyzed to investigate the role of Cdk5 in podocyte development and glomerular disease. While mice with podocyte-specific knockout of Cdk5 had no developmental defects and regular lifespan, loss of Cdk5 in podocytes increased susceptibility to glomerular damage in the nephrotoxic nephritis model. Glomerular damage was associated with reduced anti-apoptotic signals in Cdk5-deficient mice. In summary, Cdk5 acts primarily as master regulator of podocyte survival during glomerular disease and—in contrast to neurons—does not impact on glomerular development or maintenance.

scholarly journals Immune complex orchitis in vasectomized rabbits.

1976 ◽  
Vol 143 (2) ◽  
pp. 382-404 ◽  
Author(s):  
P E Bigazzi ◽  
L L Kosuda ◽  
K C Hsu ◽  
G A Andres
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Basement Membranes ◽  
Seminiferous Tubules ◽  
Immune Deposits ◽  
Rabbit Igg ◽  
Sperm Antigens ◽  
Immuno Globulins ◽  
Antigen Antibody ◽  
Selective Accumulation

The results of the present study show that bilaterally vasectomized rabbits with high levels of antibodies to sperm antigens frequently develop an orchitis associated with granular deposits of rabbit IgG and C3 in the basement membranes of seminiferous tubules. The immune deposits correspond in location to electron-opaque deposits seen by electron microscopy. The "membranous orchitis" is characterized by thickening of tubular basement membranes, acc-mulation of macrophages and a few polymorphonuclear leukocytes, and destruction of the basal lamina, of the Sertoli and spermatogenetic cells. The pathogenetic role of the immune deposits and the possibility that they contain antigen-antibody complexes is indicated by: (a) selective accumulation of IgG and C3 granular deposits along the basement membranes of seminiferous tubules in rabbits producing high and persistent levels of antibodies to sperm antigens; (b) the elution of immunoglobulins from tissues with chaotropic ion-containing buffers, acid buffers, or heat; (c) the observation that the immuno-globulins accumulated in the testis contain antibody to sperm antigens; and (d) the demonstration of sperm antigens in a location similar to that of IgG and C3. It is postulated that sperm antigen-antibody complexes are formed in the basement membranes of seminiferous tubules when antigens leaking out of the tubules react with specific antibody coming from the circulation. In two rabbits with higher levels of circulating antisperm antibodies and severe orchitis, granular deposits of IgG and C3 were also present in renal glomeruli. Immunoglobulins eluted from the kidneys contained antibody with antisperm activity. These findings are consistent with the hypothesis that in some vasectomized rabbits extratesticular lesions may develop by a mechanism comparable to that of chronic serum sickness.

Localization of Intracisternal a Particle Antigens in Neoplastic Cells and Preimplantation Mouse Embryos

1980 ◽  
Vol 38 ◽  
pp. 696-697
Author(s):  
Thomas T.F. Huang ◽  
Patricia G. Calarco
Keyword(s):  
Endoplasmic Reticulum ◽  
Normal Development ◽  
Mouse Embryos ◽  
Neoplastic Cells ◽  
Large Numbers ◽  
Preimplantation Mouse Embryos ◽  
Preimplantation Mouse ◽  
Intracisternal A Particle ◽  
Normal Feature

The stage specific appearance of a retravirus, termed the Intracisternal A particle (IAP) is a normal feature of early preimplantation development. To date, all feral and laboratory strains of Mus musculus and even Asian species such as Mus cervicolor and Mus pahari express the particles during the 2-8 cell stages. IAP form by budding into the endoplasmic reticulum and appear singly or as groups of donut-shaped particles within the cisternae (fig. 1). IAP are also produced in large numbers in several neoplastic cells such as certain plasmacytomas and rhabdomyosarcomas. The role of IAP, either in normal development or in neoplastic behavior, is unknown.

Stereological Analyses of Hepatocyte Ultrastructure Monitor Arsenic Liver Burdens

1980 ◽  
Vol 38 ◽  
pp. 442-443
Author(s):  
E. M. B. Sorensen ◽  
R. R. Mitchell ◽  
L. L. Graham
Keyword(s):  
Drainage System ◽  
Water Levels ◽  
Ultrastructural Changes ◽  
Hepatocyte Ultrastructure ◽  
Lepomis Cyanellus ◽  
Large Numbers ◽  
Activation Data ◽  
Water Analyses ◽  
Municipal Lake ◽  
Green Sunfish

Endemic freshwater teleosts were collected from a portion of the Navosota River drainage system which had been inadvertently contaminated with arsenic wastes from a firm manufacturing arsenical pesticides and herbicides. At the time of collection these fish were exposed to a concentration of 13.6 ppm arsenic in the water; levels ranged from 1.0 to 20.0 ppm during the four-month period prior. Scale annuli counts and prior water analyses indicated that these fish had been exposed for a lifetime. Neutron activation data showed that Lepomis cyanellus (green sunfish) had accumulated from 6.1 to 64.2 ppm arsenic in the liver, which is the major detoxification organ in arsenic poisoning. Examination of livers for ultrastructural changes revealed the presence of electron dense bodies and large numbers of autophagic vacuoles (AV) and necrotic bodies (NB) (1), as previously observed in this same species following laboratory exposures to sodium arsenate (2). In addition, abnormal lysosomes (AL), necrotic areas (NA), proliferated rough endoplasmic reticulum (RER), and fibrous bodies (FB) were observed. In order to assess whether the extent of these cellular changes was related to the concentration of arsenic in the liver, stereological measurements of the volume and surface densities of changes were compared with levels of arsenic in the livers of fish from both Municipal Lake and an area known to contain no detectable level of arsenic.

scholarly journals Spontaneous Abortion and Chikungunya Infection: Pathological Findings

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 554
Author(s):  
Natália Salomão ◽  
Michelle Brendolin ◽  
Kíssila Rabelo ◽  
Mayumi Wakimoto ◽  
Ana Maria de Filippis ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Spontaneous Abortion ◽  
Ultrastructural Changes ◽  
Rt Pcr ◽  
Chorionic Villi ◽  
Decidual Cells ◽  
Hofbauer Cells ◽  
Hematoxylin And Eosin ◽  
Maternal Fetal Transmission

Intrauterine transmission of the Chikungunya virus (CHIKV) during early pregnancy has rarely been reported, although vertical transmission has been observed in newborns. Here, we report four cases of spontaneous abortion in women who became infected with CHIKV between the 11th and 17th weeks of pregnancy. Laboratorial confirmation of the infection was conducted by RT-PCR on a urine sample for one case, and the other three were by detection of IgM anti-CHIKV antibodies. Hematoxylin and eosin (H&E) staining and an electron microscopy assay allowed us to find histopathological, such as inflammatory infiltrate in the decidua and chorionic villi, as well as areas of calcification, edema and the deposition of fibrinoid material, and ultrastructural changes, such as mitochondria with fewer cristae and ruptured membranes, endoplasmic reticulum with dilated cisterns, dispersed chromatin in the nuclei and the presence of an apoptotic body in case 1. In addition, by immunohistochemistry (IHC), we found a positivity for the anti-CHIKV antibody in cells of the endometrial glands, decidual cells, syncytiotrophoblasts, cytotrophoblasts, Hofbauer cells and decidual macrophages. Electron microscopy also helped in identifying virus-like particles in the aborted material with a diameter of 40–50 nm, which was consistent with the size of CHIKV particles in the literature. Our findings in this study suggest early maternal fetal transmission, adding more evidence on the role of CHIKV in fetal death.

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