Urinary excretion of viable podocytes in health and renal disease

Vogelmann, Stefanie U.; Nelson, W. James; Myers, Bryan D.; Lemley, Kevin V.

doi:10.1152/ajprenal.00404.2002

Cited by 299 publications

(317 citation statements)

References 24 publications

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“…Taken together, these important studies showed that a decrease in podocyte number is a significant predictor of disease progression in diabetic nephropathy. Finally, Lemley and coworkers (111) recently showed that despite injury to the mesangial cell in IgA nephropathy, a decrease in podocyte number correlated significantly with reduced renal function and global glomerulosclerosis.…”

Section: Podocyte Number Contributes To Glomerulosclerosismentioning

confidence: 98%

Podocyte Biology and Response to Injury

Mündel¹,

Shankland²

2002

Journal of the American Society of Nephrology

592

541

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The visceral glomerular epithelial cell, also called podocyte, is a terminally differentiated cell that lines the outer aspect of the glomerular basement membrane (GBM). It therefore forms the final barrier to protein loss, which explains why podocyte injury is typically associated with marked proteinuria. Indeed, all forms of nephrotic syndrome are characterized by abnormalities in the podocyte. In this review, we will provide an update of the known functions of recent podocyte-specific proteins and focus on the slit diaphragm (SD) and the mechanisms underlying foot process (FP) flattening and how the podocyte responds to injury. Molecular Anatomy of the Podocyte FP CytoskeletonPodocyte FP are not static, but rather contain a contractile system similar to that seen in pericytes. This contractile apparatus is composed of actin, myosin-II, ␣-actinin-4, talin, and vinculin (1). The actin filament bundles form arches between adjacent FP of the same podocyte (2). Figure 1 is a schema of our current understanding of the molecular composition of the cytoskeleton in podocyte FP. Importantly, the actin filaments are connected to the underlying GBM at focal contacts via an ␣3␤1 integrin complex (3,4). The bends of the actin filament arches appear to be connected directly to the microtubules of the major processes (own unpublished results). FP are anchored to the GBM via ␣3␤1 integrin (5) and dystroglycans (6,7). Neighboring FP are connected by a cell-cell junction, the glomerular SD, which represents the main size selective filter barrier in the kidney (8 -10). The SD is thought to be a modified adherens junction (11) that is composed of a growing number of proteins, including nephrin (12-14), P-cadherin, CD2AP (15-18), , FAT (20), podocin (16,21), and possibly Neph1 (see reference 22 and below). In addition to the contractile proteins described above, we have reported the association of synaptopodin with the actin filaments in FP (23). Synaptopodin is the first member of a novel class of prolinerich proteins (24) and, like ␣-actinin-4, interacts with the tight junction protein MAGI-1 (25) that is also expressed in podocytes (26). Four Major Causes of FP EffacementThe basolateral portion of the foot processes represents the center of podocyte function and is defined by three membrane domains: the apical membrane domain, the SD protein complex, and the basal membrane domain or sole plate (27). The submembranous regions of all compartments are connected to the FP actin cytoskeleton, e.g., on the apical membrane domain, podocalyxin associates with the actin cytoskeleton through interactions with ezrin and the actin cytoskeleton via Na ϩ /H ϩ -exchanger regulatory factor 2 (NHERF2), a scaffold protein containing two PDZ (PSD-95/Dlg/ZO-1) domains and an ERM-binding region (28,29). The FP actin cytoskeleton is highly dynamic and ultimately determines the structural maintenance of the filtration slits as demonstrated in the acute PS/heparin model by several groups (30 -32). Interference with one of the three domains eventually ...

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Section: Podocyte Number Contributes To Glomerulosclerosismentioning

confidence: 98%

Podocyte Biology and Response to Injury

Mündel¹,

Shankland²

2002

Journal of the American Society of Nephrology

592

541

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“…This finding suggests that the elevated urinary FSP1 levels are due in part to podocytes undergoing epithelial-mesenchymal transition and detaching from the glomerular basement membrane. [17][18][19] We previously reported that the appearance of FSP1 in podocytes of diabetic patients is associated with more severe clinical and pathologic findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through an epithelial-mesenchymal transitionlike phenomenon. 11 Urinary FSP1 may therefore be a novel risk factor for glomerular damage due to podocyte detachment, even in patients without crescent formation.…”

Section: Fsp1 It Was Recently Reported That Fsp1mentioning

confidence: 99%

Urinary FSP1 Is a Biomarker of Crescentic GN

Iwano

Yamaguchi²,

Iwamoto³

et al. 2012

Journal of the American Society of Nephrology

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Fibroblast-specific protein 1 (FSP1)-expressing cells accumulate in damaged kidneys, but whether urinary FSP1 could serve as a biomarker of active renal injury is unknown. We measured urinary FSP1 in 147 patients with various types of glomerular disease using ELISA. Patients with crescentic GN, with or without antinuclear cytoplasmic antibody-associated GN, exhibited elevated levels of urinary FSP1. This assay had a sensitivity of 91.7% and a specificity of 90.2% for crescentic GN in this sample of patients. Moreover, we found that urinary FSP1 became undetectable after successful treatment, suggesting the possible use of FSP1 levels to monitor disease activity over time. Urinary FSP1 levels correlated positively with the number of FSP1-positive glomerular cells, predominantly podocytes and cellular crescents, the likely source of urinary FSP1. Even in patients without crescent formation, patients with high levels of urinary FSP1 had large numbers of FSP1-positive podocytes. Taken together, these data suggest the potential use of urinary FSP1 to screen for active and ongoing glomerular damage, such as the formation of cellular crescents.

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“…Moreover, Hara et al . demonstrated the presence of many binucleate podocytes in the urine of patients affected by FSGS [94, 95] and lupus nephritis [95], suggesting that podocytes carrying nuclear abnormalities generated during an abnormal cytokinesis are more susceptible to detachment and loss.…”

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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Urinary excretion of viable podocytes in health and renal disease

Cited by 299 publications

References 24 publications

Podocyte Biology and Response to Injury

Podocyte Biology and Response to Injury

Urinary FSP1 Is a Biomarker of Crescentic GN

Podocyte Mitosis – A Catastrophe

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