Crescent-Forming Mechanism in an Irreversible Thy-1 Model in Rats

Oyanagi, Akihisa; Orikasa, Michiaki; Kawachi, Hiroshi; Ito, Yumi; Koike, Hiroko; Gejo, Fumitake; Shimizu, Fujio

doi:10.1159/000046117

Cited by 7 publications

(11 citation statements)

References 11 publications

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“…CCN1-negative podocytes may contribute to the pathological lesion seen in IgAN in two ways: first, a decrease in GBM-bound CCN1 may enhance mesangial migration, which leads to glomerular tuft occlusion and to glomerulosclerosis. Second, excessive podocyte migration can lead to podocyte bridging, and further on to glomerular crescent formation (17,20,23,26,30,31). The functional significance of CCN1 downregulation in IgAN should await further clarification.…”

Section: Discussionmentioning

confidence: 99%

Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney

Sawai¹,

Mukoyama²,

Mori³

et al. 2007

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 99%

Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney

Sawai¹,

Mukoyama²,

Mori³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Extensive studies of anti-Thy1 models of glomerulonephritis have previously been performed (1,3,4,10,11,16,17,18); the overall course of the disease, the mechanisms of disease biogenesis, and even many details of repair regulation are known. However, the multiform lesions encountered in glomeruli and tubules have never been integrated into a unified concept of damage development.…”

Section: Discussionmentioning

confidence: 99%

Pathways to Recovery and Loss of Nephrons in Anti-Thy-1 Nephritis

Kriz¹,

Hähnel²,

Hosser³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The present histopathologic study of anti-Thy-1.1 models of mesangioproliferative glomerulonephritis in rats provides a structural analysis of damage development and of pathways to recovery and to nephron loss. As long as the disease remains confined to the endocapillary compartment, the damage may be resolved or recover with a mesangial scar. Irreversible lesions with loss of nephrons emerge from extracapillary processes with crucial involvement of podocytes, leading to tuft adhesions to Bowman's capsule (BC) and subsequent crescent formation. Two mechanisms appeared to be responsible: (1) Epithelial cell proliferation at BC and the urinary orifice and (2) misdirected filtration and filtrate spreading on the outer aspect of the nephron. Both may lead to obstruction of the tubule, disconnection from the glomerulus, and subsequent degeneration of the entire nephron. No evidence emerged to suggest that the kind of focal interstitial proliferation associated with the degeneration of injured nephrons was harmful to a neighboring healthy nephron.Glomerular diseases starting with mesangiolysis have a high probability of recovery. However, not all nephrons recover; some always undergo destruction; we therefore raised the following questions: (1) what is the crucial stage of damage that determines the subsequent recovery or progression and (2) what are the sequences of events leading either to the restitution or to the degeneration of the respective nephron? Thus, our primary question was not why a nephron degenerated or recovered but how these outcomes were achieved. A glomerulus, and all the more a nephron, are both complex structures; we therefore wanted to analyze to which extent the loss and, on the other hand, the reestablishment of the higher order structure were decisive for damage progression and recovery, respectively.The most common models used to study mesangiolysis and damage development starting therefrom are those that induce mesangial cell lysis with antibodies against the Thy 1.1 antigen of mesangial cells; the resulting disease is generally referred to as anti-Thy-1 nephritis. The classical experiments were performed either with polyclonal antibodies (1,2) or with the monoclonal antibody OX-7 (3). More recently, the monoclonal antibody 1-22-3 (4) has been shown to produce more severe damage. Administration of these antibodies in rats leads to a brisk complement-dependent lysis of the mesangial cells followed by the development of a mesangioproliferative glomerulonephritis.We used both the OX-7 and the 1-22-3 antibodies in two originally separate studies. Because disease development was more or less identical in both models, we combined both studies. This permitted us to analyze complete pathways of damage development and to provide step-by-step sequences of events leading from mesangiolysis via various intermediate stages to either the recovery or loss of a nephron. We think that these results are of considerable general interest when asking how nephrons degenerate in chronic renal disease. M...

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“…[33][34][35] Although Thy-1 nephritis is basically MsPGN, crescents were observed in some studies of Thy-1 nephritis as reported by us and another study group. 13,36,37 In our previous study, treatment with prednisolone for rat Thy-1 nephritis inhibited both crescent formation and mesangial cell proliferation, although prednisolone does not suppress fibrin precipitation in Bowman's space; 36 therefore, the use of a specific factor Xa inhibitor may take advantage of antithrombotic and antiproliferative effects in crescent formation in MsPGN.…”

Section: Roles Of Factor Xa In Rat Mspgnmentioning

confidence: 92%

“…It has been reported that acute injury of the glomerulus in Thy-1 nephritis is mainly initiated by necrosis 12 and apoptosis of mesangial cells, and is often accompanied by cellular crescent formation. 13 Subsequent mesangial cell proliferation is an important pathophysiological phenomenon found in various glomerular diseases, often resulting in end-stage renal disease. 14 The aim of the present study, therefore, was to clarify the roles of the coagulation process in proliferative responses in MsPGN.…”

mentioning

confidence: 99%

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

Nomura

Liu

Nagai

et al. 2007

Laboratory Investigation

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Tissue factor initiates the extrinsic coagulation pathway by activating coagulation factor X to factor Xa, and factor V is a cofactor for the prothrombin activation by factor Xa. As factor Xa is known to promote the proliferation of mesangial cells in culture, the roles of the coagulation pathway and factor Xa were studied in an animal model of mesangioproliferative glomerulonephritis (MsPGN). MsPGN was induced in Wistar rats by an intravenous injection of anti-Thy 1.1 monoclonal antibody, OX-7. To clarify the role of factor Xa in MsPGN, a specific factor Xa inhibitor, DX-9065a, was injected intravenously at 2.5 or 10 mg/kg at the same time as OX-7, and kidney involvement was assessed by immunohistological analyses. We also examined p44/42 mitogen-activated protein (MAP) kinase activation. Time-course study revealed that expressions of tissue factor, factor V, and protease-activated receptor 2 (PAR2) were peaked on day 3, followed by factor X accumulation and mesangial proliferation. DX-9065a treatment significantly ameliorated proteinuria in a dose-dependent manner on day 8. Histological analyses showed a significant reduction in the size of glomeruli, the total number of glomerular cells, and crescent formation by DX-9065a treatment. Macrophage infiltration, which was rapidly observed on day 1 in disease control rats was not inhibited on days 1-3 by DX-9065a treatment, however it was suppressed on days 5-8. The deposition of fibrin, the number of PCNA-positive cells, and phosphorylation of p44/42 MAP kinase were markedly increased in the disease control group, whereas they were significantly reduced in the treatment group. Tissue factor and factor V induction may accelerate MsPGN through the activation and accumulation of factor X via proinflammatory and procoagulant mechanisms, and the inhibition of factor Xa would be a promising method to regulate the disease process.

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Crescent-Forming Mechanism in an Irreversible Thy-1 Model in Rats

Cited by 7 publications

References 11 publications

Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney

Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney

Pathways to Recovery and Loss of Nephrons in Anti-Thy-1 Nephritis

Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis

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