Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis

Kriz, Wilhelm; Hähnel, Brunhilde; Rösener, Sigrid; Elger, Marlies

doi:10.1038/ki.1995.433

Cited by 180 publications

(143 citation statements)

References 35 publications

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“…Because only WT-1-positive nuclei were assessed, our data can not differentiate between true podocyte cell division and the appearance of binucleated or multinucleated podocytes. In agreement with observations of this study (Figures 1 and 4D), the latter have been detected in glomerulosclerosis in situ (9,37), as well as in the urine (10,12). Because multinucleated cells can only be identified if the cell is sectioned at the level of both or more nuclei, the real percentage of binucleated or multinucleated podocytes likely is underestimated.…”

Section: Discussionsupporting

confidence: 78%

Urinary Podocyte Loss Is a More Specific Marker of Ongoing Glomerular Damage than Proteinuria

Yu¹,

Petermann²,

Kunter³

et al. 2005

Journal of the American Society of Nephrology

236

195

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Podocyte loss contributes to the development of glomerulosclerosis. Although podocyte detachment has been recognized as a new mechanism of podocyte loss in glomerular diseases, its time course and relationship to disease activity are not known. Urinary excretion of viable podocytes was quantified in two models of transient glomerular injury, i.e., rats with puromycin aminonucleoside-induced nephrosis (PAN) and mesangioproliferative nephropathy (anti-Thy 1.1 nephritis model), as well as in a model of continuous glomerular injury, i.e., hypertensive nephropathy (5/6-nephrectomy model), and in aging rats. The number of glomerular Wilm's tumor (WT)-1-positive podocytes and the glomerular expression of cell-cycle proteins in vivo were assessed. Urinary podocyte loss occurred in both primary (PAN) and secondary (anti-Thy 1.1 nephritis) in parallel to the onset of proteinuria. However, subsequently proteinuria persisted despite remission of podocyturia. In continuous glomerular injury, i.e., after 5/6-nephrectomy, podocyturia paralleled the course of proteinuria and of systemic hypertension, whereas no podocyturia became detectable during normal aging (up to 12 mo). Despite podocyte detachment of varying degrees, no decrease in glomerular podocyte counts (i.e., WT-1 positive nuclei) was noted in either disease model. Podocyturia in the PAN and anti-Thy 1.1 nephritis model was preceded by entry of glomerular podocytes into the cell cycle, i.e., cyclin D1, cdc2, and/or proliferating cell nuclear antigen (PCNA) expression. Podocyturia is a widespread phenomenon in glomerular disease and not simply a reflection of proteinuria because it is limited to phases of ongoing glomerular injury. The data suggest that podocyturia may become a more sensitive means to assess the activity of glomerular damage than proteinuria.

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Section: Discussionsupporting

confidence: 78%

Urinary Podocyte Loss Is a More Specific Marker of Ongoing Glomerular Damage than Proteinuria

Yu¹,

Petermann²,

Kunter³

et al. 2005

Journal of the American Society of Nephrology

236

195

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“…There was no evidence of a nephron-to-nephron transfer of the disease at the level of the tubulointerstitium. This conclusion is in full agreement with previous studies of the Thy-1 model (63,64), with studies of several degenerative models of nephron loss (9,46,(65)(66)(67), as well as with studies of human cases (13,68).…”

Section: Relevance Of Tubulointerstitial Processessupporting

confidence: 81%

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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“…In addition, persistent activation of Notch in podocytes leads to podocyte loss and FSGS [75]. Although mitotic catastro-phe was not previously described as a mechanism of podocyte death, the presence of multinucleated podocytes has been non-specifically reported also in other experimental [79-86] as well human [87-92] glomerulopathies (Table 1 ). For example, the presence of mitotic and multinucleated podocytes associated with heavy proteinuria and frequent glomerulosclerosis was reported as a consequence of forced re-entry into the cell cycle induced in rats by repeated injections of basic fibroblast growth factor (FGF) [79, 80].…”

Section: The Podocyte’s Catastrophe: Lost Cell Cycle Controlmentioning

confidence: 99%

“…Podocytes did not proliferate and lesions resembled classical synechiae. Interestingly, binucleate podocytes seemed to show foot process retraction with derangement of actin filaments [79, 80]. Forced cell cycle reentry of podocytes has been recently described as a consequence of conditional overexpression of telomerase reverse transcriptase (TERT) in transgenic mice [93].…”

Section: The Podocyte’s Catastrophe: Lost Cell Cycle Controlmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis

Cited by 180 publications

References 35 publications

Urinary Podocyte Loss Is a More Specific Marker of Ongoing Glomerular Damage than Proteinuria

Urinary Podocyte Loss Is a More Specific Marker of Ongoing Glomerular Damage than Proteinuria

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

Podocyte Mitosis – A Catastrophe

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