Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis)

Chen, Dilys; Jefferson, Barbara; Harvey, Scott J.; Zheng, Keqin; Gartley, Cathy; Jacobs, Robert M.; Thorner, Paul

doi:10.1097/01.asn.0000046964.15831.16

Cited by 77 publications

(43 citation statements)

References 33 publications

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“…Other studies in the Alport model have also separated antifibrotic effects from improvement in kidney function. 51,52 Given the growing evidence implicating ␣v␤6 as a component of the TGF-␤ axis, the above findings suggest that in renal fibrosis, TGF-␤ function may be central to regulation of kidney inflammation and fibroblast activation but is not critical for the regulation of podocyte-GBM interactions and GBM remodeling.…”

Section: Discussionmentioning

confidence: 99%

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

178

132

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The transforming growth factor (TGF)-␤-inducible integrin ␣v␤6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-␤. Herein , we show that ␣v␤6 is overexpressed in human kidney epithelium in membranous glomerulonephritis , diabetes mellitus , IgA nephropathy , Goodpasture's syndrome , and Alport syndrome renal epithelium. To assess the potential regulatory role of ␣v␤6 in renal disease , we studied the effects of functionblocking ␣v␤6 monoclonal antibodies (mAbs) and genetic ablation of the ␤6 subunit on kidney fibrosis in Col4A3 ؊/؊ mice , a mouse model of Alport syndrome. Expression of ␣v␤6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with ␣v␤6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in ␤6-deficient Alport mice. Transcript profiling of kidney tissues showed that ␣v␤6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-␤ RII treatment , suggesting shared regulatory functions of ␣v␤6 and TGF-␤. These findings demonstrate that ␣v␤6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm

Lukashev

Luo

et al. 2007

The American Journal of Pathology

178

132

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“…1). In addition to the effectiveness in glomerular diseases that are thought to be immunologically mediated, CNIs are also used to reduce proteinuria in Alport syndrome, which is a clear non-immunological disease caused by mutations of the type IV collagen of the GBM [42][43][44], further supporting the notion of additional CNI-mediated effects independent of T cells. Additional evidence derives from studies in children with genetic podocytopathies.…”

Section: Calcineurin Inhibitorsmentioning

confidence: 96%

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Müller-Deile

Schiffer

2015

Pediatr Nephrol

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Several of the drugs currently used for the treatment of glomerular diseases are prescribed for their immunotherapeutic or anti-inflammatory properties, based on the current understanding that glomerular diseases are mediated by immune responses. In recent years our understanding of podocytic signalling pathways and the crucial role of genetic predispositions in the pathology of glomerular diseases has broadened. Delineation of those signalling pathways supports the hypothesis that several of the medications and immunosuppressive agents used to treat glomerular diseases directly target glomerular podocytes. Several central downstream signalling pathways merge into regulatory pathways of the podocytic actin cytoskeleton and its connection to the slit diaphragm. The slit diaphragm and the cytoskeleton of the foot process represent a functional unit. A breakdown of the cytoskeletal backbone of the foot processes leads to internalization of slit diaphragm molecules, and internalization of slit diaphragm components in turn negatively affects cytoskeletal signalling pathways. Podocytes display a remarkable ability to recover from complete effacement and to re-form interdigitating foot processes and intact slit diaphragms after pharmacological intervention. This ability indicates an active insideout signalling machinery which stabilizes integrin complex formations and triggers the recycling of slit diaphragm molecules from intracellular compartments to the cell surface. In this review we summarize current evidence from patient studies and model organisms on the direct impact of immunosuppressive and supportive drugs on podocyte signalling pathways. We highlight new therapeutic targets that may open novel opportunities to enhance and stabilize inside-out pathways in podocytes.

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“…4,5 There are also reports in which immunosuppressive therapy, such as cyclosporine A, has been shown to be useful for this syndrome in dogs and humans, but it is controversial to use an immunosuppressive agent in view of adverse effects. 6,7 Gene therapy for this hereditary disease might thus be a potentially effective treatment modality. Heikkila et al 8,9 developed a method that delivered the target gene by organ perfusion and achieved high fixed rate to the kidney in the pig; however, the long-term effects were not evaluated, and, therefore, its efficacy remains unclear.…”

mentioning

confidence: 99%

Irradiation Prolongs Survival of Alport Mice

Katayama¹,

Kawano²,

Naito³

et al. 2008

Journal of the American Society of Nephrology

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Alport syndrome is a hereditary nephropathy that results in irreversible, progressive renal failure. Recent reports suggested that bone marrow transplantation (BMT) has a beneficial, short-term effect on renal injury in Alport (Col4a3 Ϫ/Ϫ ) mice, but its long-term effects, especially with regard to survival, are unknown. In this study, Alport mice received a transplant of either wild-type or Col4a3 Ϫ/Ϫ bone marrow cells. Surprising, laboratory evaluations and renal histology demonstrated similar findings in both transplanted groups. Transplanted cells accounted for Ͼ10% of glomerular cells at 8 wk, but type IV collagen ␣3 chains were not detected in glomerular basement membranes of either group by immunofluorescence or Western blot analysis, although Col4a3 mRNA in the kidney could be amplified by reverse transcription-PCR in knockout mice that received a transplant of wild-type bone marrow. Both transplanted groups, however, survived approximately 1.5 times longer than untreated knockout mice (log rank P Ͻ 0.05). These data suggested that irradiation, which preceded BMT, may have conferred a survival benefit; therefore, the survival time of knockout mice was assessed after sublethal irradiation (3, 6, and 7 Gy) without subsequent BMT. A strong positive correlation between irradiation dosage and survival time was identified (P Ͻ 0.0001). In conclusion, the improved survival observed in Alport mice that received a transplant of wild-type bone marrow might be primarily attributed to as-yet-unidentified effects of irradiation.

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Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis)

Cited by 77 publications

References 33 publications

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

αvβ6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?

Irradiation Prolongs Survival of Alport Mice

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