A new function for parietal epithelial cells: a second glomerular barrier

Ohse, Takamoto; Chang, Alice M.; Pippin, Jeffrey W.; Jarad, George; Hudkins, Kelly L.; Alpers, Charles E.; Miner, Jeffrey H.; Shankland, Stuart J.

doi:10.1152/ajprenal.00214.2009

Cited by 66 publications

(71 citation statements)

References 12 publications

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“…PECs in SSeCKS À/À mice also exhibited no discernable ultrastructural defects, forming tight junctions that appear to be normal (Figure 4d and Supplementary Figure 3). 19,25 This recapitulates the remarkable redundancy of cell-cycle mechanisms to preserve the overall development, structure, and function of the glomerulus in the absence of injurious insults.…”

Section: Phenotype Of Pecs In Ssecks à/à Micementioning

confidence: 81%

“…Archival formalin-fixed, paraffin-embedded kidneys from pre-natal mice at embryonic day 18 (E18), cyclin D1 À/À mice, diseased Tg26 mice (Tg26), diseased mice with nephrotoxic nephritis (NTN), diseased rats with passive Heymann nephritis (PHN), diseased rats with puromycin aminonucleoside nephrosis (PAN), and diseased mice with adriamycin nephrosis (AN), and the development of C57Bl/6 SSeCKS À/À and SSeCKS þ / þ (wild-type) mice, are described previously. 7,[19][20][21][22] Kidneys from male SSeCKS þ / þ and male SSeCKS À/À mice at 15 weeks of age were fixed in Karnovsky's solution for imaging glomerular ultrastructure by the University of Washington Pathology Research Service Laboratory on a Tecnai G2 Spirit Bio Twin Electron Microscope. Magnetic-bead isolation of capsulated and decapsulated glomeruli from wild-type mice following differential size sieving of digested kidneys was performed as described previously, 23 with isolated glomeruli immediately lysed in RIPA buffer (Teknova, Hollister, CA, USA) containing Complete Protease Inhibitor (Roche, Indianapolis, IN, USA), 50 mM sodium fluoride and 0.1 mM sodium orthovanadate at 41C to collect total protein.…”

Section: Materials and Methods Micementioning

confidence: 99%

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SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

Burnworth

Pippin

Karna

et al. 2012

Laboratory Investigation

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Glomerular parietal epithelial cells (PECs) are precursors to podocytes in mature glomeruli; however, as progenitors, the distinct intrinsic mechanisms that allow for repeated periods of cell-cycle arrest and re-entry of PECs after glomerulogenesis are unknown. Here, we show that the Src-suppressed protein kinase C substrate (SSeCKS), a multivalent scaffolding A kinase anchoring protein, sequesters cyclin D1 in the cytoplasm of quiescent PECs. SSeCKS expression is induced in embryonic PECs, but not in embryonic podocytes, starting at the S phase of glomerulogenesis, and is constitutively expressed postnatally by PECs, but not podocytes, in normal glomeruli. Cyclin D1 was immunoprecipitated with SSeCKS from capsulated glomeruli containing PECs, whereas decapsulated glomeruli without PECs lacked SSeCKS and cyclin D1. Cell-cell contact inhibition of proliferation in cultured PECs induced SSeCKS expression and binding of cyclin D1 by SSeCKS in the cytoplasm, whereas phosphorylation of SSeCKS by activated protein kinase C disrupted binding, resulting in nuclear translocation of cyclin D1. SSeCKS À/À mice showed hyperplasia of PECs in otherwise normal glomeruli and developed significantly worse proteinuric glomerular disease, marked by increased PEC proliferation and expression of nuclear cyclin D1, from nephrotoxic nephritis. These results suggest that SSeCKS controls the localization and activity of cyclin D1 in PECs and influences proliferative injury in the glomerulus.

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Section: Phenotype Of Pecs In Ssecks à/à Micementioning

confidence: 81%

Section: Materials and Methods Micementioning

confidence: 99%

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

Burnworth

Pippin

Karna

et al. 2012

Laboratory Investigation

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“…Adjacent PECs adherent to the underlying Bowman's basement membrane exhibit tight junctions, and express the tight junction proteins claudin-1, occludin, and ZO-1 in normal rat, mouse, and human glomeruli [25]. Tight junctions are disrupted in experimental anti-glomerular basement membrane (GBM) disease, accompanied by reduced levels of these tight junction proteins [25].…”

Section: Role Of Parietal Epithelial Cells and Filtered Albuminmentioning

confidence: 99%

“…Tight junctions are disrupted in experimental anti-glomerular basement membrane (GBM) disease, accompanied by reduced levels of these tight junction proteins [25]. In an attempt to determine the biological consequences of these changes, an in-vivo permeability assay was performed using different-sized labeled tracers.…”

Section: Role Of Parietal Epithelial Cells and Filtered Albuminmentioning

confidence: 99%

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Shankland

Anders

Romagnani

2013

Current Opinion in Nephrology and Hypertension

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Purpose of reviewWe have summarized recently published glomerular parietal epithelial cell (PEC) research, focusing on their roles in glomerular development and physiology, and in certain glomerular diseases. The rationale is that PECs have been largely ignored until the recent availability of cell lineage tracing studies, human and murine PEC culture systems, and potential therapeutic interventions of PECs. Recent findingsSeveral new paradigms involving PECs have emerged demonstrating their significant contribution to glomerular physiology and numerous glomerular diseases. A subset of PECs serving as podocyte progenitors have been identified in normal human glomeruli. They provide a source for podocytes in adolescent mice, and their numbers increase in states of podocyte depletion. PEC progenitor number is increased by retinoids and angiotensin-converting enzyme inhibition. However, dysregulated growth of PEC progenitors leads to pseudo-crescent and crescent formation. In focal segmental glomerulosclerosis, considered a podocyte disease, activated PECs increase extracellular matrix production, which leads to synechial attachment and, when they move to the glomerular tuft, to segmental glomerulosclerosis. Finally, PECs might be adversely affected in proteinuric states by undergoing apoptosis. SummaryPECs play a critical role in glomerular repair through their progenitor function, but under certain circumstances paradoxically contribute to deterioration by augmenting scarring and crescent formation.

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“…They are interconnected by tight junctions, which prevent the leakage of urine from the urinary space into the periglomerular compartment. 1 Currently, PECs have taken the center stage of attention for their contribution to glomerular diseases and as potential podocyte progenitor cells in glomerular regeneration. 2 PECs are derived from the metanephric mesenchyme.…”

mentioning

confidence: 99%

MicroRNA-193a Regulates the Transdifferentiation of Human Parietal Epithelial Cells toward a Podocyte Phenotype

Kietzmann

Guhr

Meyer

et al. 2015

Journal of the American Society of Nephrology

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Parietal epithelial cells have been identified as potential progenitor cells in glomerular regeneration, but the molecular mechanisms underlying this process are not fully defined. Here, we established an immortalized polyclonal human parietal epithelial cell (hPEC) line from naive human Bowman's capsule cells isolated by mechanical microdissection. These hPECs expressed high levels of PEC-specific proteins and microRNA-193a (miR-193a), a suppressor of podocyte differentiation through downregulation of Wilms' tumor 1 in mice. We then investigated the function of miR-193a in the establishment of podocyte and PEC identity and determined whether inhibition of miR-193a influences the behavior of PECs in glomerular disease. After stable knockdown of miR-193a, hPECs adopted a podocyte-like morphology and marker expression, with decreased expression levels of PEC markers. In mice, inhibition of miR-193a by complementary locked nucleic acids resulted in an upregulation of the podocyte proteins synaptopodin and Wilms' tumor 1. Conversely, overexpression of miR-193a in vivo resulted in the upregulation of PEC markers and the loss of podocyte markers in isolated glomeruli. Inhibition of miR-193a in a mouse model of nephrotoxic nephritis resulted in reduced crescent formation and decreased proteinuria. Together, these results show the establishment of a human PEC line and suggest that miR-193a functions as a master switch, such that glomerular epithelial cells with high levels of miR-193a adopt a PEC phenotype and cells with low levels of miR-193a adopt a podocyte phenotype. miR-193a-mediated maintenance of PECs in an undifferentiated reactive state might be a prerequisite for PEC proliferation and migration in crescent formation.

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A new function for parietal epithelial cells: a second glomerular barrier

Cited by 66 publications

References 12 publications

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

MicroRNA-193a Regulates the Transdifferentiation of Human Parietal Epithelial Cells toward a Podocyte Phenotype

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