Circulating Permeability Factors in Focal Segmental Glomerulosclerosis: In Vitro Detection

Veissi, Susan; Smeets, Bart; Wijk, J. A. E. van; Classens, René; Velden, Thea J A M van der; Jeronimus-Klaasen, Annelies; Veltkamp, Floor; Nienhuis, E.M. Mak –; Morello, William; Montini, Giovanni; Bouts, Antonia H.; Heuvel, L.P.W.J. van den; Schreuder, Michiel F.

doi:10.1016/j.ekir.2022.09.014

Cited by 7 publications

(12 citation statements)

References 51 publications

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“…In the current study, we use an in vitro model of cultured conditionally immortalized human podocytes and plasmapheresis (PP) samples (as a source of CPFs) of selected iNS patients with active disease. With this model, we recently showed that CPFs cause oxidative stress and actin cytoskeleton rearrangement in podocytes, both of which are considered hallmark events in the pathogenesis of NS [9]. Using RNA sequencing, we demonstrate in the current study that levamisole alters the expression of many actin-binding and actinremodeling proteins and functionally show that levamisole prevents actin cytoskeleton damage through GR activation and probably through subsequent actin regulating guanine triphosphate (GTPase) RhoA upregulation in podocytes exposed to NS patient plasma.…”

Section: Introductionmentioning

confidence: 54%

“…Informed consent from all subjects was obtained. Patient samples were obtained as described previously [9]. Briefly, NS samples termed "active" were the first 500 mL of plasmapheresis (PP) samples from patients with steroid-resistant NS who required PP when immunosuppressive therapy alone (calcineurin inhibitor with or without the addition of rituximab) failed to induce remission.…”

Section: Patient Materialsmentioning

confidence: 99%

“…Podocytes (10,000 cells/well) were seeded on black 96-well tissue culture plate (Greiner Bio-One, Biosigma, Italy) and grown at 33 • C with 5% CO 2 until 80% confluency, whereafter cells were transferred to 37 • C with 5% CO 2 for differentiation. After 7-10 days, podocytes were stimulated with Lipopolysaccharide (LPS; O111) 20 µg/mL, puromycin aminonucleoside (PAN) 60 µg/mL, NS plasma, or control plasma (8% supplemented with FBS to retrieve 10% plasma [9]) in the presence or absence of GR inhibitor RU486 for 6 h followed by levamisole treatment (1 µM) for 24 h. Next, cells were fixed and stained as previously described [9]. Images were obtained with a Zeiss LSM880 laser scanning microscope (Zeiss, Oberkochen, Germany) using standard filter sets.…”

Section: Immunofluorescence Imagingmentioning

confidence: 99%

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Levamisole Modulation of Podocytes’ Actin Cytoskeleton in Nephrotic Syndrome

Veissi,

van den Berge,

van Wijk

et al. 2023

Biomedicines

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Podocytes play a central role in glomerular diseases such as (idiopathic) nephrotic syndrome (iNS). Glucocorticoids are the gold standard therapy for iNS. Nevertheless, frequent relapses are common. In children with iNS, steroid-sparing agents are used to avoid prolonged steroid use and reduce steroid toxicity. Levamisole is one of these steroid-sparing drugs and although clinical effectiveness has been demonstrated, the molecular mechanisms of how levamisole exerts its beneficial effects remains poorly studied. Apart from immunomodulatory capacities, nonimmunological effects of levamisole on podocytes have also been suggested. We aimed to elaborate on the effects of levamisole on human podocytes in iNS. RNA sequencing data from a human podocyte cell line treated with levamisole showed that levamisole modulates the expression of various genes involved in actin cytoskeleton stabilization and remodeling. Functional experiments showed that podocytes exposed to puromycin aminonucleoside (PAN), lipopolysaccharides (LPS), and NS patient plasma resulted in significant actin cytoskeleton derangement, reduced cell motility, and impaired cellular adhesion when compared to controls, effects that could be restored by levamisole. Mechanistic studies revealed that levamisole exerts its beneficial effects on podocytes by signaling through the glucocorticoid receptor and by regulating the activity of Rho GTPases. In summary, our data show that levamisole exerts beneficial effects on podocytes by stabilizing the actin cytoskeleton in a glucocorticoid receptor-dependent manner.

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Section: Introductionmentioning

confidence: 54%

Section: Patient Materialsmentioning

confidence: 99%

Section: Immunofluorescence Imagingmentioning

confidence: 99%

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Levamisole Modulation of Podocytes’ Actin Cytoskeleton in Nephrotic Syndrome

Veissi,

van den Berge,

van Wijk

et al. 2023

Biomedicines

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“…Veissi et al obtained samples from patients with relapsing FSGS in kidney transplant at start and completion of plasmapheresis. Upon 24 h exposure of 10% patient plasma to immortalized podocytes, there was evidence of cell detachment, membrane blebbing, and podocyte rounding consistent with apoptotic death of cells [11]. These findings were not seen in patient samples from those who did not have FSGS or who had FSGS in remission.…”

Section: Role Of Circulating Factorsmentioning

confidence: 90%

“…Additional analysis showed disruption of actin cytoskeleton and reactive oxygen species present in recurrent FSGS plasma exposed to podocytes versus membranous, minimal change, or controls. In vitro analysis is a possible tool to track and monitor in vivo CPF activity based on this study [11,12].…”

Section: Role Of Circulating Factorsmentioning

confidence: 99%

Current approaches to overcome recurrent focal segmental glomerulosclerosis after kidney transplantation

Ahmad,

Peleg,

Ahn

2023

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of review Recurrent focal segmental glomerulosclerosis (FSGS) presents with nephrotic syndrome shortly after kidney transplantation. This review will overview the role of circulating permeability factors in disease pathogenesis and treatment options for recurrent FSGS. Recent findings Novel circulating permeability factors have been identified in serum samples. Current research is focused on detection of permeability factors as a marker of treatment response. Furthermore, novel monoclonal antibodies are being utilized to further induce remission. Summary Posttransplant recurrent FSGS can have a deleterious effect on allograft. Early detection of disease recurrence with prompt treatment is optimal for clinical remission. Plasmapheresis with anti-B cell therapy is considered the mainstay of treatment. Newer B cell therapies and detection of circulating factors in serum may help in providing targeted treatment in a subset of patients.

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