Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate

Wharram, Bryan L.; Goyal, Meera; Gillespie, Patrick J.; Wiggins, Jocelyn; Kershaw, David B.; Holzman, Lawrence B.; Dysko, Robert C.; Saunders, Thomas L.; Samuelson, Linda C.; Wiggins, Roger C.

doi:10.1172/jci7236

Cited by 146 publications

(119 citation statements)

References 25 publications

(21 reference statements)

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“…Foot processes are widened, intermediate filament distribution is altered, and mice have lower GFR despite the absence of albuminuria. This model in particular supports the notion that specific and separable functions can be assigned to the various gene products that cause mouse and human podocytopathies (84).…”

Section: The Possible and The Actual: Animal Modelssupporting

confidence: 78%

Inherited Podocytopathies

Pollak¹

2002

Journal of the American Society of Nephrology

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Section: The Possible and The Actual: Animal Modelssupporting

confidence: 78%

Inherited Podocytopathies

Pollak¹

2002

Journal of the American Society of Nephrology

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“…Loss of glomerular foot process associates with uncoupling of podocalyxin from the actin cytoskeleton [11]. Another protein located on the apical cell membrane of foot process is the glomerular epithelial protein 1 ( GLEPP-1 ), a receptor tyrosine phosphatase involved in regulation of the podocyte cytoskeletal protein probably through direct or indirect interactions with vimentin [13]. …”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

“…Recently, mutations in myosin 1E ( MYO1E ) an actin-dependent molecular motor, are associated with childhood-onset, glucocorticoid-resistant FSGS [41]. Finally, GLEPP1 - null mice do not exhibit proteinuria, but podocytes display morphological changes, such as broadening of the foot process [13]. The slit diaphragm interactome is still growing, and the biological significance of individual molecules and interactions still needs clarification by future research.…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

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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“…The targeting approach used for knockout was, however, specific for the full-length isoform. 67 Further, since these mice were not challenged with a carcinogen, it is difficult to assess the effect of the PTPRO deletion in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

Jacob

Motiwala

2005

Cancer Gene Ther

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Promoter methylation-mediated silencing is a hallmark of many established tumor suppressor genes. This review focuses on the methylation and suppression of a receptor-type tyrosine phosphatase gene, PTPRO, in a variety of solid and liquid tumors. In addition, PTPRO exhibits many other characteristics of a bona fide tumor suppressor. Reactivation of genes silenced by methylation using inhibitors of DNA methyltransferases and histone deacetylases, and the potential application of PTPRO as a molecular target for cancer therapy have been discussed.

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Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate

Cited by 146 publications

References 25 publications

Inherited Podocytopathies

Inherited Podocytopathies

Podocyte Mitosis – A Catastrophe

Epigenetic regulation of protein tyrosine phosphatases: potential molecular targets for cancer therapy

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