Collapsing Glomerulopathy

Albaqumi, Mamdouh; Soos, Timothy; Barisoni, Laura; Nelson, Peter J.

doi:10.1681/asn.2006030225

Cited by 145 publications

(193 citation statements)

References 123 publications

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“…Consistent with this more severe pathology, SSeCKS À/À mice with NTN exhibit 10-fold greater proteinuria than SSeCKS þ / þ mice with NTN (Figure 6d), out of proportion to percent crescent formation, suggesting loss of GFB more characteristic of collapsing glomerulopathy than crescentic glomerulonephritis. 32,33 We confirmed that proliferating PECs accounted for the more severe extracapillary lesions in SSeCKS À/À mice with NTN. Staining and quantification of the number of PAX8-positive cells in diseased glomeruli showed a significantly higher number of PECs in proliferative lesions present in SSeCKS À/À mice compared with SSeCKS þ / þ mice (Figure 6e-g).…”

Section: Expression Of Ssecks In Models Of Podocytopathiessupporting

confidence: 70%

“…In both crescentic glomerulonephritis and collapsing glomerulopathy, cells derived from PECs are now known to be major constituents of these extracapillary lesions, possibly representing an aberrant hyperplastic repair response by PECs. [3][4][5] We hypothesized earlier that patterns of aberrant repair in the proliferative podocytopathies lie on a spectrum of inflammatory injury, [32][33][34] recently identifying the TNF-a-TNFR2 axis as one possible causative pathway. 27,28 Intriguingly, TNF-a is one of a host of mitogenic activators of PKC, 26 inducing PKC phosphorylation of SSeCKS in PECs.…”

Section: Expression Of Ssecks In Models Of Podocytopathiesmentioning

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: Expression Of Ssecks In Models Of Podocytopathiessupporting

confidence: 70%

Section: Expression Of Ssecks In Models Of Podocytopathiesmentioning

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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“…The possibility that IFN could participate in collapsing glomerulopathies related to viral infections such as HIV and parvovirus B19 deserves further study. A central role for activation of the Th1 response has been proposed for some forms of collapsing FSGS (57). It remains to be determined how IFN may alter the synthesis of other, potentially pathogenic cytokines, such as IL-6 or IL-13 family members, which have been incriminated as permeability factors in FSGS and MCD (58,59).…”

Section: Discussionmentioning

confidence: 99%

Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Markowitz¹,

Nasr²,

Stokes³

et al. 2010

Clinical Journal of the American Society of Nephrology

191

170

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Background and objectives: Treatment with IFN is rarely associated with nephrotic syndrome and renal biopsy findings of minimal-change disease or FSGS.Design, setting, participants, & measurements: We report 11 cases of collapsing FSGS that developed during treatment with IFN and improved after discontinuation of therapy.Results: The cohort consists of seven women and four men with a mean age of 48.2 yr. Ten of the 11 patients were black. Six patients were receiving IFN-␣ for hepatitis C virus infection (n ‫؍‬ 5) or malignant melanoma (n ‫؍‬ 1), three were receiving IFN-␤ for multiple sclerosis, and two were treated with IFN-␥ for idiopathic pulmonary fibrosis. After a mean and median duration of therapy of 4.0 and 12.6 months, respectively, patients presented with acute renal failure (mean creatinine 3.5 mg/dl) and nephrotic-range proteinuria (mean 24-hour urine protein 9.7 g). Renal biopsy revealed collapsing FSGS with extensive foot process effacement and many endothelial tubuloreticular inclusions. Follow-up was available for 10 patients, all of whom discontinued IFN. At a mean of 23.6 months, nine of 10 patients had improvement in renal function, including one with complete remission and two with partial remission. Among the seven patients with available data, mean proteinuria declined from 9.9 to 3.0 g/d. Four of the seven patients were treated with immunosuppression, and there was no detectable benefit.Conclusions: Collapsing FSGS may occur after treatment with IFN-␣, -␤, or -␥ and is typically accompanied by the ultrastructural finding of endothelial tubuloreticular inclusions. Optimal therapy includes discontinuation of IFN.

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“…Electron microscopy demonstrates characteristic glomerular basement membrane folding and wrinkling within the collapsed loops, frequently leading to partial capillary lumen occlusions. Immunohistochemical staining of podocytes reveals upregulated markers of proliferation and downregulated markers of differentiation (48). Hence, dysregulation of the glomerular epithelial phenotype with consequent dedifferentiation, proliferation, and apoptosis leads to loss of glomerular architecture and is thought to be a principal mechanism of glomerulosclerosis in HIVAN.…”

Section: Genetic Susceptibility and Hivanmentioning

confidence: 99%

Genetic Susceptibility, HIV Infection, and the Kidney

Kiryluk

Martino

Gharavi

2007

Clinical Journal of the American Society of Nephrology

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In recent years, the sequencing of mammalian and microbial genomes has provided the opportunity to study how genetic variation in the host and pathogen influence the course of infectious disease. In the case of HIV-1 infection, such studies have led to identification of key viral proteins that determine pathogenicity, immune evasion, or drug resistance. In addition, candidate gene association studies have uncovered a large number of host genetic variants that influence the outcome of infection and some organ-specific complications. HIV-associated nephropathy (HIVAN) is a pathologically distinct complication of HIV infection. Interindividual variability in incidence, skewed ethnic distribution, and familial aggregation of HIVAN with other forms of ESRD have suggested genetic susceptibility as a major contributing factor. This article reviews the host genetic factors that influence the course of HIV-1 infection and discusses murine models that have increased the understanding of HIVAN pathogenesis and demonstrated the role of genetic background on determination of disease.

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Collapsing Glomerulopathy

Cited by 145 publications

References 123 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

Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Genetic Susceptibility, HIV Infection, and the Kidney

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