α‐Actinin‐4 is involved in the process by which dexamethasone protects actin cytoskeleton stabilization from adriamycin‐induced podocyte injury

Liu, Haimei; Gao, Xia; Xu, Hong; Feng, Chun; Kuang, Xinyu; Li, Zengxia; Zha, Xiliang

doi:10.1111/j.1440-1797.2012.01645.x

Cited by 33 publications

(19 citation statements)

References 25 publications

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“…4a). As reported before [5], treatment with 0.5 μM ADR for 24 h disrupted the normal morphology of podocytes. Cell shrank to spindle-like shape and cytoplasmic actin fibers were diminished (Fig.…”

Section: Resultssupporting

confidence: 79%

Vincristine alleviates adriamycin-induced nephropathy through stabilizing actin cytoskeleton

et al. 2017

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Antimicrotubule agent vincristine (VCR) has long been known as an alternative treatment for frequent relapse nephrotic syndrome and steroid-dependent nephrotic syndrome (SDNS). However, the mechanism is unknown. Here we found that VCR at a dosage much lower than that as an antimicrotubule agent can alleviate adriamycin (ADR)-induced proteinuria and podocyte foot process effacement. In cultured podocytes, VCR prevents ADR-induced actin fiber disorganization. In both in vitro and in vivo models, VCR suppresses ADR-induced overexpression of α3β1 integrin and focal adhesion kinase (FAK). These data suggest that VCR may relieve ADR-induced nephropathy through inhibiting injury-induced activation of integrin outside-in signaling to prevent actin cytoskeleton remodeling. Hence, our work reveals a novel role of VCR in regulating actin fiber assembly and provides first evidence on the therapeutic mechanism of VCR on nephrotic syndrome.

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Section: Resultssupporting

confidence: 79%

Vincristine alleviates adriamycin-induced nephropathy through stabilizing actin cytoskeleton

et al. 2017

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“…These cells have a very limited capacity for repair or regeneration, so that therapeutic strategies to protect podocytes and/or promote their repair/replacement are greatly sought after [16]. Functional responses to GCs in cultured murine and human podocytes have also been suggested by expression analyses reporting several GC-regulated genes [50][51][52]. By studying our unique human podocyte cell lines we reported [13] direct effects of glucocorticosteroids (GCs, another form of drug that is very effective in patients with nephrotic syndrome, but whose use is empirical because little is known of its mode of action) on human podocytes.…”

Section: Discussionmentioning

confidence: 99%

Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte

et al. 2015

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Minimal change nephropathy (MCN) is the third most common cause of primary nephrotic syndrome in adults. Most patients with MCN respond to corticosteroid therapy, but relapse is common. In children, steroid-dependent patients are often given alternative agents to spare the use of steroids and to avoid the cumulative steroid toxicity. In this respect, levamisole has shown promise due to its ability to effectively maintain remission in children with steroid-sensitive or steroid-dependent nephrotic syndrome. Despite clinical effectiveness, there is a complete lack of molecular evidence to explain its mode of action and there are no published reports on the use of this compound in adult patients. We studied the effectiveness of levamisole in a small cohort of adult patients and also tested the hypothesis that levamisole's mode of action is attributable to its direct effects on podocytes. In the clinic, we demonstrate that in our adult patients, cohort levamisole is generally well tolerated and clinically useful. Using conditionally immortalized human podocytes, we show that levamisole is able to induce expression of glucocorticoid receptor (GR) and to activate GR signalling. Furthermore, levamisole is able to protect against podocyte injury in a puromycin aminonucleoside (PAN)-treated cell model. In this model the effects of levamisole are blocked by the GR antagonist mifepristone (RU486), suggesting that GR signalling is a critical target of levamisole's action. These results indicate that levamisole is effective in nephrotic syndrome in adults, as well as in children, and point to molecular mechanisms for this drug's actions in podocyte diseases.

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“…Disruption of actin cytoskeleton integrity is the molecular basis for podocyte foot process effacement [37][38][39][40].…”

Section: Loss Of Podocyte Gsk3β Improves Podocyte Focal Adhesions Andmentioning

confidence: 99%

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Dworkin

et al. 2016

J. Pathol.

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Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the β isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3β expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte specific somatic ablation of GSK3β in adult mice attenuated proteinuria and ameliorated podocyte injury and glomerular damage in experimental adriamycin (ADR) nephropathy. Mechanistically, actin cytoskeleton integrity in podocytes was largely preserved in GSK3β knockout mice following ADR insult, concomitant with a correction of podocyte hypermotility and lessened phosphorylation and activation of paxillin, a focal adhesion associated adaptor protein. In addition, GSK3β knockout diminished ADR induced NFκB RelA/p65 phosphorylation selectively at serine 467, suppressed de novo expression by podocytes of NFκB dependent podocytopathic mediators, including B7-1, cathepsin L and MCP-1, but barely affected the induction of NFκB target prosurvival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death was significantly attenuated in GSK3β knockout mice, associated with a protection against podocyte mitochondrial damage and reduced phosphorylation and activation of cyclophilin F, a structural component of mitochondria permeability transition pores. Overall, our findings suggest that the β isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.

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α‐Actinin‐4 is involved in the process by which dexamethasone protects actin cytoskeleton stabilization from adriamycin‐induced podocyte injury

Abstract: This study showed that dexamethasone had direct effects on podocytes: α-actinin-4 may be one of the potential target molecules.

Cited by 33 publications

References 25 publications

Vincristine alleviates adriamycin-induced nephropathy through stabilizing actin cytoskeleton

Vincristine alleviates adriamycin-induced nephropathy through stabilizing actin cytoskeleton

Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

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