Mitosis and the Presence of Binucleate Cells among Glomerular Podocytes in Diseased Human Kidneys

Nagata, Michio; Yamaguchi, Yutaka; Komatsu, Yasuhiro; Ito, Katsuhiko

doi:10.1159/000188546

Cited by 75 publications

(54 citation statements)

References 7 publications

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“…Podocytes are an essential part of the glomerular filtration barrier but cannot regenerate themselves. 40,41 Loss of podocytes beyond a certain threshold is sufficient to trigger glomerulosclerosis. 42,43 We recently showed that late in renal development, a fraction of podocytes are recruited from cells on Bowman's capsule (presumptive PECs), 25 offering the perspective that this mechanism might still be preserved in adults.…”

Section: Discussionmentioning

confidence: 99%

Origin of Parietal Podocytes in Atubular Glomeruli Mapped by Lineage Tracing

Schulte

Berger

Boor

et al. 2014

Journal of the American Society of Nephrology

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Parietal podocytes are fully differentiated podocytes lining Bowman's capsule where normally only parietal epithelial cells (PECs) are found. Parietal podocytes form throughout life and are regularly observed in human biopsies, particularly in atubular glomeruli of diseased kidneys; however, the origin of parietal podocytes is unresolved. To assess the capacity of PECs to transdifferentiate into parietal podocytes, we developed and characterized a novel method for creating atubular glomeruli by electrocoagulation of the renal cortex in mice. Electrocoagulation produced multiple atubular glomeruli containing PECs as well as parietal podocytes that projected from the vascular pole and lined Bowman's capsule. Notably, induction of cell death was evident in some PECs. In contrast, Bowman's capsules of control animals and normal glomeruli of electrocoagulated kidneys rarely contained podocytes. PECs and podocytes were traced by inducible and irreversible genetic tagging using triple transgenic mice (PEC-or Pod-rtTA/LC1/R26R). Examination of serial cryosections indicated that visceral podocytes migrated onto Bowman's capsule via the vascular stalk; direct transdifferentiation from PECs to podocytes was not observed. Similar results were obtained in a unilateral ureter obstruction model and in human diseased kidney biopsies, in which overlap of PEC-or podocyte-specific antibody staining indicative of gradual differentiation did not occur. These results suggest that induction of atubular glomeruli leads to ablation of PECs and subsequent migration of visceral podocytes onto Bowman's capsule, rather than transdifferentiation from PECs to parietal podocytes.

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Section: Discussionmentioning

confidence: 99%

Origin of Parietal Podocytes in Atubular Glomeruli Mapped by Lineage Tracing

Schulte

Berger

Boor

et al. 2014

Journal of the American Society of Nephrology

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“…27 In addition, Ki-67 positive cells were predominantly non-tagged cells, and the podocytes rarely expressed Ki-67, which indicates that podocytes can re-enter the cell cycle. 28,29 Nonetheless, this is insufficient to guarantee cell division (proliferation) even in tagged cells expressing Ki-67. Taken together, we conclude that the great majority of hyperplastic epithelial cells in this model of FSGS are of PEC origin.…”

Section: Discussionmentioning

confidence: 99%

Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis

Suzuki

Matsusaka

Nakayama

et al. 2009

The American Journal of Pathology

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Focal segmental glomerulosclerosis (FSGS) is a progressive renal disease, and the glomerular visceral cell hyperplasia typically observed in cellular/collapsing FSGS is an important pathological factor in disease progression. However, the cellular features that promote FSGS currently remain obscure. To determine both the origin and phenotypic alterations in hyperplastic cells in cellular/collapsing FSGS, the present study used a previously described FSGS model in p21-deficient mice with visceral cell hyperplasia and identified the podocyte lineage by genetic tagging. The p21-deficient mice with nephropathy showed significantly higher urinary protein levels, extracapillary hyperplastic indices on day 5, and glomerular sclerosis indices on day 14 than wild-type controls. X-gal staining and immunohistochemistry for podocyte and parietal epithelial cell (PEC) markers revealed progressive podocytopenia with capillary collapse accompanied by PEC hyperplasia leading to FSGS. In our investigation, non-tagged cells expressed neither WT1 nor nestin. Ki-67, a proliferation marker, was rarely associated with podocytes but was expressed at high levels in PECs. Both terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and electron microscopy failed to show evidence of significant podocyte apoptosis on days 5 and 14. These findings suggest that extensive podocyte loss and simultaneous PEC hyperplasia is an actual pathology that may contribute to the progression of cellular/collapsing FSGS in this mouse model. Additionally, this is the first study to demonstrate the regulatory role of p21 in the PEC cell cycle. (Am J

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“…It has been suggested that p27 Kip1 stabilizes the cell cycle of these terminally differentiated cells [36]. Increased p27 Kip1 expression is cell-protective and reflects a cellular reaction to injury or stress in podocytes [34].…”

Section: Discussionmentioning

confidence: 99%

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

et al. 2003

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Aims/hypothesis. It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. Methods. Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-β, ET-1, PDGF-AB, fibronectin, desmin and α-smooth muscle cell actin was investigated by immunohistochemistry.Results. The mean number of podocytes per glomerulus was lower (86±17 vs. 138±25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET A -RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27 kip1 positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-β. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. Conclusion/interpretation. Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET A -RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET A -receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology. [Diabetologia (2003) 46:856-868]

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Mitosis and the Presence of Binucleate Cells among Glomerular Podocytes in Diseased Human Kidneys

Cited by 75 publications

References 7 publications

Origin of Parietal Podocytes in Atubular Glomeruli Mapped by Lineage Tracing

Origin of Parietal Podocytes in Atubular Glomeruli Mapped by Lineage Tracing

Genetic Podocyte Lineage Reveals Progressive Podocytopenia with Parietal Cell Hyperplasia in a Murine Model of Cellular/Collapsing Focal Segmental Glomerulosclerosis

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy

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