Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

Wyburn, Kate; Chadban, Steven J.; Kwan, Tak; Alexander, Stephen I.; Wu, Huiling

doi:10.1152/ajprenal.00669.2011

Cited by 13 publications

(10 citation statements)

References 60 publications

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“…Renal mononuclear leukocyte infiltration is seen in renal tissues of FSGS mice [16,17,50-52]. As shown in Figure 6A, although significantly increased renal peri-glomerular infiltration of T cells (CD3 + ) was seen at days 14 and 28 in FSGS+vehicle mice compared to normal control mice (both p < 0.005), this effect was markedly inhibited in FSGS+Citral mice (both p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

et al. 2013

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The pathogenesis of focal segmental glomerulosclerosis (FSGS) is considered to be associated with oxidative stress, mononuclear leukocyte recruitment and infiltration, and matrix production and/or matrix degradation, although the exact etiology and pathogenic pathways remain to be determined. Establishment of a pathogenesis-based therapeutic strategy for the disease is clinically warranted. Citral (3,7-dimethyl-2,6-octadienal), a major active compound in Litsea cubeba , a traditional Chinese herbal medicine, can inhibit oxidant activity, macrophage and NF-κB activation. In the present study, first, we used a mouse model of FSGS with the features of glomerular epithelial hyperplasia lesions (EPHLs), a key histopathology index of progression of FSGS, peri-glomerular inflammation, and progressive glomerular hyalinosis/sclerosis. When treated with citral for 28 consecutive days at a daily dose of 200 mg/kg of body weight by gavage, the FSGS mice showed greatly reduced EPHLs, glomerular hyalinosis/sclerosis and peri-glomerular mononuclear leukocyte infiltration, suggesting that citral may be renoprotective for FSGS and act by inhibiting oxidative stress and apoptosis and early activating the Nrf2 pathway. Meanwhile, a macrophage model involved in anti-oxidative and anti-inflammatory activities was employed and confirmed the beneficial effects of citral on the FSGS model.

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Section: Resultsmentioning

confidence: 99%

Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

et al. 2013

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“…The results of the present study also indicated that, when administered at a dose previously used by Wyburn et al . () just before the first irinotecan injection, IL‐18bp protected against all of the intestinal injury‐related parameters examined, resulting in significant reductions in inflammatory reactions. It is also important to emphasize that we did not find any strain‐related differences in susceptibility to the development of intestinal mucositis between C57BL/6 and BALB/c mice, for any of the parameters studied.…”

Section: Discussionmentioning

confidence: 99%

Targeted inhibition of IL‐18 attenuates irinotecan‐induced intestinal mucositis in mice

Lima-Júnior

Freitas

Wong

et al. 2014

British J Pharmacology

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Background and Purpose Intestinal mucositis is a common side‐effect of irinotecan‐based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL‐18 is up‐regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL‐18 in the pathogenesis of irinotecan‐induced intestinal mucositis. Experimental Approach Wild type (WT), IL‐18 or caspase‐1 knockout mice were treated with either saline or irinotecan (60 mg·kg−1 per 4 days, i.p.) or the IL‐18 binding protein (IL‐18bp, 10 mg·kg−1) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL‐18 expression. Key Results Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL‐18 expression in WT mice compared with saline treatment. The IL‐18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase‐1 knockout and IL‐18 knockout mice, and in IL‐18bp‐treated WT mice. Furthermore, the Survival of irinotecan‐treated mice was increased and iNOS immunoexpression and IL‐18 production prevented in IL‐18 knockout mice. Conclusions and Implications Targeting IL‐18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens.

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“…The degree of glomerulosclerosis was defined by the presence of PAS-positive staining material involving >30% of each glomerulus. Eighty to one-hundred glomeruli per animal from random, non-overlapping cortical regions were scored to determine the percentage of glomeruli displaying glomerulosclerosis [21]. Interstitial fibrosis was quantified by point counting of the trichrome-stained interstitium and expressed as a percentage of the total cortical area [22].…”

Section: Methodsmentioning

confidence: 99%

Resolvin D1 Protects Podocytes in Adriamycin-Induced Nephropathy through Modulation of 14-3-3β Acetylation

Zhang

Sun

et al. 2013

PLoS ONE

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Resolvin D1 (RvD1) is a lipid-derived mediator generated during the resolution inflammation. While the immunoresolvent effects of Resolvins have been extensively studied in leukocytes, actions of Resolvins on intrinsic kidney cells have received little attention. The podocyte plays a central role in glomerular function, and podocyte damage can lead to proteinuria and glomerulosclerosis. This study examined whether RvD1 has renoprotective effects upon podocytes. We investigated a mouse model of adriamycin (ADR) nephropathy featuring rapid induction of podocyte damage and proteinuria followed by glomerulosclerosis. We identified a progressive loss of synaptopodin expression over a 28 day time-course of ADR nephropathy which was associated with increased acetylation of 14-3-3β and reduced synaptopodin phosphorylation. Groups of mice were given once daily RvD1 treatment (4 ng/g body weight/day) starting either 30 min (early treatment) or 14 days (late treatment) after ADR injection and continued until mice were killed on day 28. Early, but not late, RvD1 treatment attenuated ADR-induced proteinuria, glomerulosclerosis and tubulointerstitial fibrosis, modified macrophages from an M1 to M2 phenotype. Early RvD1 treatment prevented the down-regulation of synaptopodin expression and changes in 14-3-3β acetylation and synaptopodin phosphorylation. In a podocyte cell line, RvD1 was shown to prevent rapid TNF-α-induced down-regulation of synaptopodin expression. In transfection studies, TNF-α-induced a decrease in synaptopodin phosphorylation and an increase in acetylation of 14-3-3β, resulting in disassociation between 14-3-3β and synaptopodin. RvD1 prevented TNF-α induced post-translational modification of synaptopodin and 14-3-3β proteins, and maintained the synaptopodin/14-3-3β interaction. Furthermore, replacement of lysine K51, or K117+K122 in 14-3-3β with glutamine, to mimic lysine acetylation, significantly reduced the interaction between 14-3-3β and synaptopodin. In conclusion, our studies provide the first evidence that RvD1 can protect against podocyte damage by preventing down-regulation of synaptopodin through inhibition of 14-3-3β/synaptopodin dissociation. RvD1 treatment may have potential application in the treatment of chronic kidney disease.

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Interleukin-18 binding protein therapy is protective in adriamycin nephropathy

Cited by 13 publications

References 60 publications

Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

Citral Is Renoprotective for Focal Segmental Glomerulosclerosis by Inhibiting Oxidative Stress and Apoptosis and Activating Nrf2 Pathway in Mice

Targeted inhibition of IL‐18 attenuates irinotecan‐induced intestinal mucositis in mice

Resolvin D1 Protects Podocytes in Adriamycin-Induced Nephropathy through Modulation of 14-3-3β Acetylation

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