Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.

Baker, Andrew R.; Mooney, Andrew; Hughes, Jeremy; Lombardi, Donna; Johnson, Richard J.; Savill, John

doi:10.1172/jci117565

Cited by 381 publications

(301 citation statements)

References 42 publications

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“…In the end, the lesion manifested as segmental glomerulosclerosis, frequently associated with a fibrocellular crescent. From previous studies (34,35,36) and from hints in the present study (in the 10-wk group of rats, 20.2% of glomerular profiles were classified as intact, i.e., exhibiting slim mesangial axes Table 2), we know that scar tissue within the mesangium and a crescent may in the long run be subject to a remodeling process, leading to a decrease in its volume. However, we were unable to find a decrease in the ratio of glomeruli with tuft adhesion between the middle and last groups of animals in either of the studies (Table 2).…”

Section: Mechanisms Leading To Recovery or Repairsupporting

confidence: 64%

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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Section: Mechanisms Leading To Recovery or Repairsupporting

confidence: 64%

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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“…NF-B plays an important role in the survival of various cells, including mesangial cells (47,48). Blunted activation of NF-B may lead to glomerular cell apoptosis that is required for clearance of excessive mesangial cells during the resolution of mesangial proliferative glomerulonephritis (49). Similarly, lack of AP-1 activation may lead to suppression of glomerular cell proliferation (50).…”

Section: Discussionmentioning

confidence: 99%

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Hayakawa

Meng

Hiramatsu

et al. 2006

The Journal of Immunology

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Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. Activated macrophages trigger mesangial cells to express an array of inflammation-associated genes via activation of NF-κB and AP-1. However, this inflammatory response is often transient and subsides spontaneously. We found that mesangial cells activated by bystander macrophages showed blunted responses of NF-κB to subsequent macrophage exposure. It was associated with sustained levels of IκBβ, but not IκBα. The tolerance observed was reversible and reproduced by conditioned media from activated macrophages (macrophage-conditioned medium (MφCM)). In vivo priming of mesangial cells by activated glomerular macrophages also caused the tolerance of mesangial cells. The macrophage-derived tolerance inducers were heat-labile, and multiple molecules were involved. Among inflammatory cytokines produced by macrophages, TNF-α and IL-1β were able to induce mesangial cell tolerance dose-dependently. The mesangial cell tolerance was also observed in activation of the MAPK-AP-1 pathway; i.e., phosphorylation of ERK, JNK, and p38 MAPK by macrophages was blunted when the cells were pre-exposed to MφCM. Induction of c-fos and c-jun was also abrogated in mesangial cells pre-exposed to MφCM, and the suppression was attenuated by blockade of MAPK activation during the first exposure to MφCM. These data elucidated that mesangial cells, once exposed to macrophages, become insensitive to subsequent activation by macrophages and proinflammatory stimuli. This self defense of glomerular cells may play a role in the resolution of macrophage-mediated, acute glomerulonephritis.

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“…Apoptosis has been implicated as a cell deletion mechanism for removal of excess mesangial cells, endothelial cells and GECs during progressive glomerulosclerosis in many experimental models. [39][40][41] Apoptosis may serve to prevent the propagation of damaged DNA to daughter cells. In our study of human IgAN, we have demonstrated increased apoptotic activity in glomeruli in advanced-stage disease (subgroup C), which is highly correlated with the overexpression of pro-proliferative CCPs.…”

Section: Discussionmentioning

confidence: 99%

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

Qiu

Sinniah

Hsu

2004

Laboratory Investigation

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The activities of cell cycle regulatory proteins have been reported to be associated with the development of pathological lesions in glomerulonephritis. To assess the cellular mechanisms underlying the mesangial cell proliferation and glomerulosclerosis in progressive human IgA nephropathy (IgAN), we examined the expression of E2F1, Rb, c-Myc, proliferating cell nuclear antigen (PCNA), cyclins (D1, E and A), cyclindependent kinase 2 (CDK2) and CDK inhibitors (p21 waf1 , p27 kip1 , 57 kip2 and p16 ink4a ) by immunohistochemistry in renal biopsy specimens. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was also performed to detect the presence of apoptosis. In total, 51 cases of IgAN were categorized into four subgroups according to histological severity. A dramatic upregulation of E2F1 expression in mesangial cells was identified in proliferating glomeruli, which correlated well with the proliferation index. High endogenous expression of p27 kip1 and p57 kip2 by podocytes in normal glomeruli and glomeruli with minor lesions was observed to decrease in proliferating and sclerosing glomeruli; this pattern displayed a strong inverse correlation with the mean glomerulosclerosis score and the index of glomerular lesion. Increased apoptotic activity was identified in progressive glomerular lesions of advanced IgAN, which correlated with the proliferative activity in these lesions as assessed by total expression levels of PCNA and CDK2 in glomeruli, E2F1 expression levels in the mesangium, cyclin D1 expression levels in endothelium and the c-Myc glomerular staining score. Our results suggest that the onset and magnitude of mesangial cell proliferation and glomerulosclerosis is associated with the upregulation of E2F1 by mesangial cells and the downregulation of p27 kip1 and p57 kip2 by glomerular epithelial cells. The cell type-specific and coordinated regulation of proliferative and proapoptotic activities of cell cycle regulatory proteins may play an important role in mediating progressive glomerular injury in human IgAN. Laboratory Investigation (2004) 84, 1112-1125, advance online publication, 21 June 2004 doi:10.1038/labinvest.3700144 Keywords: IgA nephropathy; cell cycle regulatory protein; mesangial cell proliferation; glomerulosclerosis; apoptosis Cell cycle regulatory proteins (CCPs) govern not only cellular hypertrophy and proliferation, but also cellular apoptosis and differentiation. Mounting evidence has emerged that indicates a close link between cell cycle regulation and the development of histopathological lesions in glomerular diseases. 1,2 In the experimental model of mesangial proliferative anti-Thy1.1 nephritis, increased expression of cyclins A, D1 and cyclin-dependent kinase 2 (CDK2) by mesangial cells in association with decreased high endogenous levels of CDK inhibitor (CKI) p27 kip1 by glomerular epithelial cells (GECs), were required for mesangial cell proliferation. [3][4][5] The increased glomerular activity of CDK2 could be inhibited by the CDK antagonist r...

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Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.

Abstract: Increases in mesangial cell number may herald glomerular scarring, but they are not irreversible. This study sought mechanisms by which surplus glomerular mesangial cells can be cleared. A small proportion of cultured mesangial cells exhibited typical morphological features of apoptosis

Cited by 381 publications

References 42 publications

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

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

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Role of differential and cell type-specific expression of cell cycle regulatory proteins in mediating progressive glomerular injury in human IgA nephropathy

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