Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis

Meyer-Schwesinger, Catherine; Dehde, Silke; Sachs, Marlies; Mathey, Sabrina; Arefi, Kazem; Gatzemeier, Stefan; Balabanov, Stefan; Becker, Jan U.; Thaiss, Friedrich; Meyer, Tobias

doi:10.1152/ajprenal.00380.2011

Cited by 14 publications

(9 citation statements)

References 48 publications

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“…In the present study, MPGN podocytes showed not only morphological changes but also abnormalities in SD protein localization; nephrin, podocin, and synaptopodin were localized to the cell body as well as FP, showing a granular pattern. More recent studies indicated that Rho-kinases play a pivotal role in the organization of the actin cytoskeleton of podocytes [38,39,40]. Asanuma et al [39] suggested that Rho-kinase regulates actin-myosin-containing stress fibers in the podocyte cell body.…”

Section: Discussionmentioning

confidence: 99%

“…Asanuma et al [39] suggested that Rho-kinase regulates actin-myosin-containing stress fibers in the podocyte cell body. Meyer-Schwesinger et al [[40] demonstrated that increased activation of Rho-kinases leads to cytoskeletal rearrangement in the course of antibody-mediated podocyte injury, culminating in FP effacement, proteinuria, and detachment into the urine, and that this could be prevented by Rho-kinase inhibition. Furthermore, in vitro and in vivo studies have revealed that proinflammatory cytokines such as IL-1β and TNF-α are involved in Rho-kinase pathway activation [41,42].…”

Section: Discussionmentioning

confidence: 99%

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Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

Kimura¹,

Ichii²,

Otsuka³

et al. 2013

Am J Nephrol

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Background: Membranous proliferative glomerulonephritis (MPGN) is a major primary cause of chronic kidney disease (CKD). Podocyte injury is crucial in the pathogenesis of glomerular disease with proteinuria, leading to CKD. To assess podocyte injuries in MPGN, the pathological features of spontaneous murine models were analyzed. Methods: The autoimmune-prone mice strains BXSB/MpJ-Yaa and B6.MRL-(D1Mit202-D1Mit403) were used as the MPGN models, and BXSB/MpJ-Yaa⁺ and C57BL/6 were used as the respective controls. In addition to clinical parameters and glomerular histopathology, the protein and mRNA levels of podocyte functional markers were evaluated as indices for podocyte injuries. The relation between MPGN pathology and podocyte injuries was analyzed by statistical correlation. Results: Both models developed MPGN with albuminuria and elevated serum anti-double-strand DNA (dsDNA) antibody levels. BXSB/MpJ-Yaa and B6.MRL showed severe proliferative lesions with T and B cell infiltrations and membranous lesions with T cell infiltrations, respectively. Foot process effacement and microvillus-like structure formation were observed ultrastructurally in the podocytes of both MPGN models. Furthermore, both MPGN models showed a decrease in immune-positive areas of nephrin, podocin and synaptopodin in the glomerulus, and in the mRNA expression of Nphs1, Nphs2, Synpo, Actn4, Cd2ap, and Podxl in the isolated glomerulus. Significant negative correlations were detected between serum anti-dsDNA antibody levels and glomerular Nphs1 expression, and between urinary albumin-to-creatinine ratio and glomerular expression of Nphs1, Synpo, Actn4, Cd2ap, or Podxl.Conclusion: MPGN models clearly developed podocyte injuries characterized by the decreased expression of podocyte functional markers with altered morphology. These data emphasized the importance of regulation of podocyte injuries in MPGN.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

Kimura¹,

Ichii²,

Otsuka³

et al. 2013

Am J Nephrol

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“…Lysates from the stimulated cells were assessed by western blot analysis using murine anti-UCH-L1 antibody, and β-actin was used as a control for protein loading. Murine podocytes were pre-treated with PDTC at the stated concentrations for 2 h, following stimulation with (A) TNF-α ( via the immune injury mechanism (1,2,25,32,33). Studies have demonstrated that the changes to podocyte morphology and function following injury were closely associated with the abnormalities of numerous podocyte proteins, including UCH-L1, nephrin and synaptopondin (1,34,35).…”

Section: Discussionmentioning

confidence: 99%

NF-κB upregulates ubiquitin C-terminal hydrolase 1 in diseased podocytes in glomerulonephritis

Zhang

Mao

Sun

et al. 2015

Molecular Medicine Reports

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Podocyte injury is a pivotal factor during the progression of glomerular diseases. It has been demonstrated that the expression of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is increased in injured podocytes in a number of types of glomerulonephritis. However, its mechanism of regulation remains to be elucidated. A previous study by our group suggested that UCH-L1 is a downstream protein of nuclear factor (NF)-κB signaling. In the present study, the involvement of NF-κB in the regulation of the expression of UCH-L1 was investigated in diseased podocytes in vivo and in vitro. Increases in the expression of phosphorylated NF-κB at p65 and UCH-L1 were detected using immunohistochemical analysis of kidney biopsy tissues from 56 cases of nephritis, including immunoglobulin A nephropathy, membranous glomerulonephritis and lupus nephritis. The two indicators were also analyzed using western blot analysis in cultured murine podocytes stimulated by inflammatory factors. The results of the present study demonstrated that in human renal biopsies of several cases of immune complex-mediated glomerulonephritis, the increases of NF-κB and UCH-L1 were positively correlated with the number of diseased podocytes. By contrast, in non-immune complex-mediated glomerulonephritis, no clear activation of NF-κB and increase of UCH-L1 expression was observed. In vitro, immune stimulation also led to the upregulation of UCH-L1 through the NF-κB signaling pathway in mouse podocytes. In conclusion, the results of the present study suggested that the activation of NF-κB and upregulation of UCH-L1 in podocytes may be vital in podocyte injury associated with immune complex-mediated glomerulonephritis.

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“…Activation of RhoA in podocytes induces FSGS [ 20 ] with disruption of the actin cytoskeleton [ 21 ]. Rho-kinase inhibition protected podocytes and reduced proteinuria in one mouse model [ 22 ]. There is still some controversy about which protein forms the most logical target, with another recent paper suggesting that RhoA is not the key member of the family in podocytes, instead providing evidence that another Rho family GTPase, cdc42, is the key one for maintenance of the podocyte actin cytoskeleton [ 23 ].…”

Section: What About Novel More Specific Forms Of Therapy?mentioning

confidence: 99%

The podocyte cytoskeleton in health and in disease

Mathieson

2012

Clinical Kidney Journal

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The podocyte is a key cell in the selective filtering action of the glomerular capillary wall. Podocyte injury is of pathogenetic and prognostic significance in human glomerular disease; podocyte repair and regeneration are important therapeutic targets. In particular, podocyte function is dependent on the cells' actin cytoskeleton: this maintains their complex structure. Alterations in the actin cytoskeleton arise from a variety of genetic and acquired causes. Therapeutic agents that are beneficial in proteinuric disease may act at least partly by restoring the cell shape via effects on the actin cytoskeleton. Recent studies of podocytes in vivo and in vitro are described, highlighting clinically relevant observations and those that help us understand the ways in which we may harness nature's own mechanisms to repair and/or renew these specialized glomerular cells, with a particular focus on their actin cytoskeleton. Drugs that have beneficial effects on podocytes can improve our ability to treat important renal diseases including diabetic nephropathy. Currently available agents can be applied in this way and the rapid progress in the study of podocytes is highlighting new therapeutic targets that can bring even more specificity.

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Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis

Abstract: TN. Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis.

Cited by 14 publications

References 48 publications

Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

NF-κB upregulates ubiquitin C-terminal hydrolase 1 in diseased podocytes in glomerulonephritis

The podocyte cytoskeleton in health and in disease

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