Methylprednisolone Accelerates the Resolution of Glomerulonephritis by Sensitizing Mesangial Cells to Apoptosis

Maruyama, Kouichi; Kashihara, Naoki; Yamasaki, Yasushi; Sato, Minoru; Sugiyama, Hiroshi; Okamoto, Kazunori; Maeshima, Yohei; Odawara, Masahiro; Sasaki, Junzo; Makino, Hírofumi

doi:10.1159/000052627

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…These findings are in accordance with the potentiation of TNF-α-induced apoptosis of mesangial cells by the overexpression of truncated IĸBα [12]. Furthermore, in the study by Maruyama et al[ 28] administration of methylprednisolone suppressed NF-ĸB activation and ameliorated mesangial hypercellularity in the Thy1.1 GN model by decreasing glomerular proliferation and increasing apoptosis. Our present findings are consistent with their observations.…”

Section: Discussionsupporting

confidence: 75%

The Novel NF-κB Activation Inhibitor Dehydroxymethyl-Epoxyquinomicin Suppresses Anti-Thy1.1-Induced Glomerulonephritis in Rats

Kosaka

Miyajima

Kikuchi

et al. 2008

Nephron Exp Nephrol

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AbstractBackground: NF-κB participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-κB in inflammatory renal diseases. Therefore, NF-κB is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl-epoxyquinomicin (DHMEQ), a novel NF-κB activation inhibitor, on anti-thy1.1 antibody-induced glomerulonephritis (Thy1.1 GN). Methods: Thy1.1 GN was induced in Sprague-Dawley rats (6/group) by intravenous injection of anti-thy 1.1 antibody. The effects of DHMEQ (8 mg/kg/day) on the glomerular disease were evaluated using periodic acid-Schiff and Masson trichrome stains, immunohistochemistry for proliferating cell nuclear antigen, fibronectin and CD45 (leukocyte common antigen) and TUNEL staining. NF-κB activation was analyzed by a fluorescent electrophoretic mobility shift assay. Results: On day 7, DHMEQ treatment resulted in marked inhibition of NF-κB, decreased proteinuria (223.2 ± 42.3 vs. 434.8 ± 16.5 mg/kg/day, p < 0.05), preserved creatinine clearance (1.93 ± 0.38 vs. 1.07 ± 0.29 l/day, p < 0.01), decreased glomerular cell proliferation (15.8 ± 1.2 vs. 31.2 ± 0.8 nuclei/glomerular cross-section) and mesangial matrix deposition, and an increase in glomerular and tubular apoptosis without inducing any obvious adverse effects. Conclusion: DHMEQ inhibited NF-κB and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN.

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Section: Discussionsupporting

confidence: 75%

The Novel NF-κB Activation Inhibitor Dehydroxymethyl-Epoxyquinomicin Suppresses Anti-Thy1.1-Induced Glomerulonephritis in Rats

Kosaka

Miyajima

Kikuchi

et al. 2008

Nephron Exp Nephrol

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“…First, it has anti-apoptotic properties and prevents cell death in cells with malignant potential. Second, NF-κB stimulates the immune response, specifically, the production of pro-inflammatory cytokines [22] , and NF-κB activation is associated with inflammation in experimental nephritis [23] . In the present study, we observed that TNF-α indirectly induced glomerulonephritis via the TNF-α/NF-κB signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Rhein lysinate increases the median survival time of SAMP10 mice: protective role in the kidney

Liu

Zhen

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the protective effects of rhein lysinate (RHL), a major bioactive constituent of the rhizome of rhubarb (Rheum palmatum Linn or Rheum tanguticum Maxim), against kidney impairment in senescence-prone inbred strain 10 (SAMP10) mice. Methods: SAMP10 mice were orally administered RHL (25 or 50 mg/kg) daily until 50% of the mice died. Senescence-resistant inbred strain 1 (SAMR1) mice administered no drug were taken as control. The kidneys were harvested after animal death, and examined morphologically and with immunochemical assays. The levels of MAD, SOD and GSH-px in the kidneys were measured with a photometric method. The expression of inflammatory factors and related proteins in the kidneys was analyzed using Western blotting. Results: Treatment of SAMP10 mice with RHL had no effect on the body weight or phenotype. However, RHL significantly prolonged the median survival time of SAMP10 mice by approximately 25%, as compared to untreated SAMP10 mice. Compared SAMR1 mice, SAMP10 mice had a significantly lower level of SOD in the kidneys, but had no significant difference in the MDA or GSH-px levels. Treatment of SAMP10 mice with RHL significantly reduced the MAD level, and increased the SOD and GSH-px levels in the kidneys. Glomerulonephritis was observed in SAMP10 mice but not in SAMR1 mice. RHL decreased the incidence of glomerulonephritis, and significantly decreased the levels of TNF-α, IL-6, NF-κB, collagen types I and III in the kidneys. Conclusion: Accelerated senescence is associated with glomerulonephritis in SAMP10 mice, and RHL prolongs their median survival time by reducing the severity of glomerulonephritis.

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“…Several lines of evidence suggest that antiproliferative effects of glucocorticoids are often accompanied by an induction of apoptosis [Amsterdam and Sasson, 2002]. Indeed, methylprednisolone ameliorates mesangial hypercellularity in glomerulonephritis by decreasing proliferating cells and increasing apoptosis [Maruyama et al, 2001]. Moreover, glucocorticoids are efficacious in the treatment of leukemia as they are inductors of apoptosis in many lymphocytes [Distelhorst, 2002].…”

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confidence: 99%

Glucocorticoids mediate differential anti‐apoptotic effects in human fibroblasts and keratinocytes via sphingosine‐1‐phosphate formation

Hammer

Sauer

Spika

et al. 2004

J of Cellular Biochemistry

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Glucocorticoids are potent anti-inflammatory and immunomodulatory drugs which also induce growth inhibition in a variety of cell types. For this reason long-term treatment of inflammatory skin diseases may result in irreversible skin atrophy. To elucidate whether the antiproliferative action of glucocorticoids in fibroblasts is accompanied by induction of apoptosis we investigated the influence of dexamethasone (DEX) on both parameters. Interestingly, we revealed that growth inhibitory concentrations of this glucocorticoid did not induce fibroblast apoptosis. Moreover, DEX protected these cells from apoptosis induced by tumor necrosis factor alpha (TNFalpha)/actinomycin, UV-irradiation, and cell permeable ceramides. These findings are in contrast to the lack of anti-apoptotic effects detected in keratinocytes. Although DEX inhibited TNFalpha mediated nuclear factor-kappa (NF-kappaB) activity in fibroblasts, this mechanism was not involved in its cytoprotection as it was verified by specific NF-kappaB inhibitors. Therefore, we looked for alternative intracellular mediators. Coincubation of fibroblasts with the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocks formation of the sphingolipid degradation product sphingosine-1-phosphate (S1P), abrogated the protective glucocorticoid effect almost completely. As preincubation with S1P reduced the number of apoptotic cells after stimulation with TNFalpha/actinomycin and moreover DEX increased the intracellular S1P content a role of this sphingolipid in the cytoprotection by DEX is suggested.

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Methylprednisolone Accelerates the Resolution of Glomerulonephritis by Sensitizing Mesangial Cells to Apoptosis

Cited by 9 publications

References 46 publications

The Novel NF-κB Activation Inhibitor Dehydroxymethyl-Epoxyquinomicin Suppresses Anti-Thy1.1-Induced Glomerulonephritis in Rats

The Novel NF-κB Activation Inhibitor Dehydroxymethyl-Epoxyquinomicin Suppresses Anti-Thy1.1-Induced Glomerulonephritis in Rats

Rhein lysinate increases the median survival time of SAMP10 mice: protective role in the kidney

Glucocorticoids mediate differential anti‐apoptotic effects in human fibroblasts and keratinocytes via sphingosine‐1‐phosphate formation

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