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Results for “Passive Heyman nephritis”

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PubMed1983

Severe glomerular epithelial cell damage does not prevent passive Heyman nephritis in rats.

Passive Heymann nephritis (PHN) is an experimental model of membranous glomerulopathy in the rat ascribed to in situ formation of immune complexes. Very recently the demonstration that the aminonucleoside of puromycin provides some protection against PHN has highlighted the role of intrinsic properties of the glomerulus in immune complex formation. Adriamycin, a widely employed chemotherapeutic agent, is known to induce a nephrotic syndrome in rats characterized by severe ultrastructural changes of glomerular epithelial cells and by loss of glomerular polyanionic charges. We have studied the effect of pre-treatment with adriamycin on glomerular immune deposits in PHN using immunomorphological and quantitative techniques. In normal rats (group 1) injection of heterologous antibodies to proximal tubular brush border antigen (anti-FxIA), rapidly induces subepithelial immune deposits, as observed by immunofluorescence. Pre-treatment of rats with adriamycin (group 2) 48 hr before injection of anti-FxIA antibodies, when proteinuria is absent, does not alter the immunohistological findings of PHN. Heavily proteinuric rats (group 3) pre-treated with adriamycin 13 days before injection of anti-FxIA did not show any significant difference from groups 1 and 2. Species binding of injected anti-FxIA antibodies, studied by paired label techniques, was similar in normal rats and in proteinuric and non-proteinuric rats treated with adriamycin. The only difference was in the group of proteinuric rats treated with adriamycin, in which at 5 hr binding in the kidney was higher, due to tubular brush border binding as shown by immunofluorescence. This study indicates that local changes of the glomerulus and loss of glomerular histochemical properties do not invariably alter the glomerular deposition of immune complexes.

Animals↗
PubMed2004

Inhibitory effects of ligustrazine, a modulator of thromboxane-prostacycline-nitric oxide balance, on renal injury in rats with passive Heyman nephritis.

AIMS: To explore the effects of ligustrazine on proteinuria, urinary TxB2 (metabolism of thromboxane A2, TxA2) and 6-keto-PGF1alpha (metabolism of prostacyclines I2, PG I2), glomerular inducible nitric oxide(NO) synthase (iNOS) mRNA, urinary NO3-/NO2- (decomposing products of NO) and pathological changes in rats with passive Heymann nephritis (PHN). METHODS: A rat PHN model was induced by intravenous injection of rabbit anti-rat renal tubular antigen (Tub-Ag) antiserum, and ligustrazine was given intraperitoneally into PHN rats every 2 days for 1-5 weeks. Then, proteinuria, urinary TxB2 and 6-keto-PGF1alpha, glomerular iNOS mRNA, and urinary NO3-/NO2- were measured by sulfosalicylic acid, radioimmunoassay (RIA), Northern blot and nitric acid reductase methods, respectively. Moreover, the damage to the renal tissue of the rats was observed under light and electron microscopy and immunofluorescence (IF). RESULTS: The urinary TxB2 in PHN rats was significantly higher than that in control rats, but the PHN rats treated with ligustrazine had significantly less proteinuria, urinary TxB2 and tissue lesions, and more urinary 6-keto-PGF(1alpha), glomerular iNOS mRNA and urinary NO2-/NO3- than the PHN rats without the administration of ligustrazine. CONCLUSION: These data indicate that ligustrazine has inhibitory roles on the glomerular injury of PHN rats, which may associate with modulating the balance of TxA2-PGI2 and elevating synthesis of NO to a certain extent.

6-Ketoprostaglandin F1 alpha↗
PubMed2026

LCM-Enriched Proteomic Characterization of Antibody-Mediated Glomerular Damage and Complement Activation in Pre-Clinical Models.

Biologics, lipid nanoparticles, and other therapeutic modalities can result in adverse events, often detected as lesions during preclinical pathology assessments. Characterization of these lesions provides valuable information during drug development to contextualize mechanisms of injury and assess species translatability. Here, we investigated the utility of a laser capture microdissection (LCM)-enriched mass spectrometry proteomics approach to analyze two well-characterized preclinical models of regional (glomerular) injury: Passive Heyman Nephritis in rats and bovine gamma globulin-induced glomerular injury in nonhuman primates (NHPs). Using LCM-enriched proteomics, glomeruli were isolated from formalin-fixed paraffin-embedded kidney tissue in the rat model, enabling identification of 4,661 proteins and quantification of 3,410. Proteinuria measurements were compared with digital pathology metrics of glomerular morphology and proteomics results, with all modalities yielding concordant evidence of glomerular injury and proteomics confirming the role of complement activation. The same LCM- enriched proteomics workflow was applied to an NHP model of induced glomerular damage, identifying 4,623 proteins, quantifying 3,000, and confirming qualitative concordance with established features of complement-mediated glomerular injury. Together, these findings illustrate the applicability of LCM-enriched proteomics for region-specific characterization of antibody-mediated tissue injury and support its use as a hypothesis-generating platform in translational toxicologic pathology.

Animals↗
PubMed1995

The effects of soluble recombinant complement receptor 1 on complement-mediated experimental glomerulonephritis.

Complement is a major mediator of tissue injury in several types of glomerulonephritis. However, no therapeutic agents that inhibit complement activation are available for human use. sCR1 (TP10, BRL 55736) is a recombinant, soluble human complement receptor 1 (CR1) molecule lacking transmembrane and cytoplasmic domains that inhibits C3 and C5 convertase activity by preferentially binding C4b and C3b. To test the efficacy of sCR1 on complement-mediated glomerulonephritis, rats were pretreated with sCR1 (60 mg/kg per day) before and during the induction of three models of complement-dependent glomerulonephritis (concanavalin A and antithymocyte serum models of proliferative glomerulonephritis, passive Heyman nephritis). Daily sCR1 and complement hemolytic activity levels were measured, and renal histology and urine protein excretion were examined. Mean serum sCR1 levels of 100 to 200 micrograms/mL were maintained with a reduction in complement hemolytic activity to less than 15% in most animals. In the antithymocyte serum model, sCR1-treated animals had significant reductions in mesangiolysis, glomerular platelet and macrophage infiltrates, and proteinuria at 48 h. In the concanavalin A model, sCR1 significantly reduced glomerular C3 and fibrin deposits, platelet infiltrates, and proteinuria at 48 h. In passive Heymann nephritis, proteinuria was also significantly reduced (199 +/- 8.5 versus 125 +/- 16 mg/day, P < 0.002) at 5 days. It was concluded that sCR1 significantly reduces both morphologic and functional consequences of several different types of complement-mediated glomerulonephritis and deserves evaluation as a potential therapeutic agent in complement-mediated immune glomerular disease in humans.

Animals↗
PubMed1996

SPARC is expressed in renal interstitial fibrosis and in renal vascular injury.

Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet, the pathophysiology of the injury remains obscure. We investigated the expression of SPARC (secreted protein acidic and rich in cysteine) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansion in rats. SPARC is a secreted glycoprotein that has been demonstrated to affect cellular interaction with matrix proteins, modulate cell proliferation, bind to and/or inhibit growth factors such as PDGF and bFGF, and regulate angiogenesis. Interstitial expression of SPARC was most prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser extent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRNA were substantially increased at sites of tubulointerstitial fibrosis/matrix expansion. In the PHN model, SPARC protein was expressed by interstitial fibroblasts that also produced alpha-smooth muscle actin ("myofibroblasts") and correlated both temporally (r = 0.97) and spatially with sites of type I collagen deposition. Interstitial cell proliferation preceded the development of interstitial fibrosis, and maximal SPARC expression (d15) coincided with the initial decline in interstitial proliferation. In the Ang II-infusion model, which is characterized by arteriolopathy and tubulointerstitial injury, an increase in SPARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cells in the adventitia of hypertrophied arteries. In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model. In addition to its proposed role in extracellular matrix deposition. the antiproliferative properties of SPARC might contribute to the resolution of interstitial fibroblast proliferation in the PHN model.

Actins↗
PubMed2002

Obstructive nephropathy and renal fibrosis.

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Animals↗
PubMed2005

Y-box protein 1 mediates PDGF-B effects in mesangioproliferative glomerular disease.

The pivotal role of PDGF-B for mesangioproliferative glomerular disease is well established. Here, Y-box protein-1 (YB-1) was identified as a downstream signaling target of PDGF-B. In healthy kidney cells, YB-1 was located predominantly within the nuclear compartment. Subsequent to PDGF-B infusion and in the course of anti-Thy1.1-induced mesangioproliferative glomerulonephritis, relocalization of YB-1 into the cytoplasm was observed. In experimental models that lack profound mesangial cell proliferation (e.g., Puromycin-nephrosis, passive Heyman nephritis, spontaneous normotensive nephrosclerosis, hyperlipidemic diabetic nephropathy), YB-1 remained nuclear. This translocation coincided with upregulation of YB-1 protein levels within the mesangial compartment. Increased YB-1 expression and subcellular shuttling was dependent on PDGF-B signaling via the mitogen-activated protein kinase pathway because these alterations were prevented by specific PDGF aptamers and the mitogen-activated protein kinase pathway inhibitor U0126. Furthermore, PDGF-B strongly induced YB-1 expression in vitro. This induction was important because RNAi-dependent knockdown of YB-1 abolished the mitogenic PDGF-B effect. Taken together, YB-1 seems to represent a specific and necessary PDGF-B target in mesangioproliferative glomerular disease.

Animals↗