The mTOR Inhibitor Everolimus Attenuates the Time Course of Chronic Anti-Thy1 Nephritis in the Rat

Wittmann, Sandra K.; Daniel, Christoph; Braun, Andrea; Vogelbacher, Regina; Shimizu, Fuijo; Kawachi, Hiroshi; Hugo, Christian

doi:10.1159/000116112

Cited by 22 publications

(25 citation statements)

References 71 publications

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“…In addition, 14 male anti-Thy1 nephritic Sprague Dawley rats were used in a second experiment using seven rats per TSP-2 and lacZ control group for investigation of glomerular isolates. Glomeruli were isolated by a standard sieving procedure (38) on days 3 and 6 after nephritis induction. For investigation of the phenotype of TSP-2 overexpression in healthy rats, we used six rats each treated either with the TSP-2 or lacZ expression vector.…”

Section: Methodsmentioning

confidence: 99%

“…Rat MC were cultured from isolated glomeruli using a standard sieving procedure (38) and characterized by positive staining for ␣-smooth muscle actin and ␣ 8-integrin and the lack of the epithelial marker synaptopodin, endothelial marker RECA-1, and the macrophage/monocyte marker CD68. MC were grown in DMEM containing 10% FCS, insulin (5 g/ml), and penicillin/streptomycin at 37°C and 5% CO 2.…”

Section: Methodsmentioning

confidence: 99%

“…The isolation of glomeruli and the quantification of glomerular target proteins by real-time PCR were performed as described (38).…”

Section: Methodsmentioning

confidence: 99%

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Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation

Daniel

Wagner

Hohenstein

et al. 2009

American Journal of Physiology-Renal Physiology

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We recently identified thrombospondin-2 (TSP-2) as an endogenous regulator of matrix remodelling and inflammation in experimental kidney disease by studying TSP-2-deficient mice. In this study, we asked whether systemic TSP-2 overexpression via thigh muscle transfection is able to ameliorate the time course of the anti-Thy1 glomerulonephritis model. After induction of anti-Thy1 nephritis, rats were transfected either with an overexpression plasmid for TSP-2 or lacZ as a control. Biopsies, urine, and blood samples were taken on days 1, 3, and 6 after disease induction. Muscular overexpression of TSP-2 reduced glomerular transforming growth factor (TGF)-beta activation and glomerular extracellular matrix formation as determined by collagen IV and fibronectin. In addition, activation of mesangial cells to the myofibroblast-like phenotype was also significantly decreased in TSP-2-overexpressing animals. TSP-2 overexpression inhibited both glomerular endothelial and mesangial cell proliferation, resulting in a reduced glomerular cell number and glomerular tuft area. The inflammatory response, as monitored by T cells and antigen-presenting cells, was reduced significantly by TSP-2 overexpression, but influx of macrophages was unchanged. These data demonstrate TSP-2 as a potential therapeutic agent to inhibit the glomerular proliferative and inflammatory response as well as TGF-beta activation and extracellular matrix accumulation in experimental mesangial proliferative glomerulonephritis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation

Daniel

Wagner

Hohenstein

et al. 2009

American Journal of Physiology-Renal Physiology

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“…Furthermore, it has been presumed that vascular endothelial growth factor (VEGF)-A plays a crucial role in the pathogenesis of Rapa-induced proteinuria. VEGF-A, the expression of which is decreased by mTOR inhibition (3,5,34,37), has been shown to be crucial to the glomerular integrity (10,11). In a previous study, we have shown that mTOR inhibition can have both protective and detrimental effects in a model of nephrotoxic serum nephritis (NTS).…”

mentioning

confidence: 99%

The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response

Kirsch

Riegelbauer

Tagwerker

et al. 2012

American Journal of Physiology-Renal Physiology

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Rapamycin (Rapa) is an immunosuppressant used to prevent rejection in recipients of renal transplants. Its clinical use is limited by de novo onset or exacerbation of preexisting proteinuria. In the present study, Rapa administration was started 14 days after induction of murine nephrotoxic serum nephritis (NTS) to study glomerular effects of this mammalian target of rapamycin (mTOR) inhibitor. Glomeruli were laser-microdissected, and real-time PCR was performed to assess effects on glomerular cells and the expression of inflammatory cytokines. Immunohistochemical stainings were performed to confirm mRNA data on the protein level. Compared with nephritic control animals, Rapa-treated mice developed significantly increased albuminuria. This was accompanied by a more prominent glomerular infiltration by CD4(+) T cells and macrophages. Glomerular mRNA expression profiling revealed increased levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor-α, and the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β and their cognate macrophage-associated receptors CCR2 and CCR5 in the Rapa-treated animals. Furthermore, there were elevated glomerular transcription levels of the regulatory T cell phenotype transcription factor Foxp3. No differences in the glomerular expression of the podocyte marker nephrin or the endothelial cell marker CD31 were observed on the mRNA or protein level. In conclusion, our data indicate that Rapa-induced proteinuria in NTS is a result of the activation of the innate immune system rather than a direct toxicity to podocytes or glomerular endothelial cells.

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“…This has been confirmed in human and mouse lupus nephritis [92], and anti-Thy1.1-induced chronic glomerulosclerosis in the rat [93,94]. Support for the importance of mTOR activation in the Thy1.1 model comes from studies in which inhibition of mTOR with rapamycin attenuates matrix accumulation, reduces proteinuria, and reduces cell proliferation [93,94]. …”

Section: Effects Of Translation On Kidney Function and Diseasesmentioning

confidence: 92%

Mechanisms and Control of Protein Translation in the Kidney

Schaeffer¹,

Abrass²

2009

Am J Nephrol

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Translational control of protein synthesis is critical for cell division, homeostasis and survival. Recent data indicate that dysregulation of protein synthesis that leads to either increased or decreased expression of specific proteins contributes to the manifestations of various kidney diseases. Most of the control of protein synthesis occurs in the first or initiation phase, which is also the most complicated. Following the initiation phase is the elongation phase where the peptide chain is formed. RNA transcripts are released from ribosomes after the termination phase. Transcripts can be translated in a cap-dependent or cap-independent manner. The mTOR (mammalian target of rapamycin) cascade regulates translation of most cap-dependent transcripts at the level of initiation and elongation, which represents 95% of total transcripts. During specific events (e.g. mitosis, stress cell survival) control of the less-common cap-independent transcripts occurs which allows the cell to adapt to the new state. Activation of stress kinases and inactivation of the mTOR pathway are at the center of this adaptive mechanism. Recent studies have elucidated the role of micro-RNAs (miRs) in controlling translation. miRs bind directly to specific transcripts and most often directly reduce translation; however, by targeting other positive or negative regulators of the pathways regulating protein synthesis they may indirectly affect synthetic levels of other transcripts. Several examples are described below in which these mechanisms are intertwined and act together to dysregulate protein synthesis in the diseased kidney.

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The mTOR Inhibitor Everolimus Attenuates the Time Course of Chronic Anti-Thy1 Nephritis in the Rat

Cited by 22 publications

References 71 publications

Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation

Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-β activation

The mTOR-inhibitor rapamycin mediates proteinuria in nephrotoxic serum nephritis by activating the innate immune response

Mechanisms and Control of Protein Translation in the Kidney

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