The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin

Stylianou, Kostas; Petrakis, Ioannis; Mavroeidi, Vasiliki; Stratakis, Stavros; Vardaki, Eleftheria; Perakis, Kostas; Stratigis, Spyros; Passam, Andreas; Papadogiorgaki, Eva; Giannakakis, K.; Nakopoulou, Lydia; Daphnis, Eugene

doi:10.1093/ndt/gfq496

Cited by 94 publications

(56 citation statements)

References 46 publications

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“…The immunological effects of sirolimus on disease mechanisms in LN require further investigation. Possible mechanisms leading to a reduction of disease activity include reduction of intra-renal lymphoproliferation and MCP-1 expression, suppression of anti-dsDNA production and immune deposition, reversal of senescent phenotype of bone marrow-derived mesenchymal cells, promotion of Treg expansion and blockade of Th17 expansion [16][17][18][27][28][29][30]. Furthermore, the results from animal experiments and human kidney biopsies demonstrating activation of the mTOR pathway during active nephritis, and the therapeutic effect of mTOR inhibitor in murine lupus, provide a strong rationale for testing the effect of mTOR inhibitors in the treatment of human LN [16,17].…”

Section: Adverse Eventsmentioning

confidence: 99%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

Yap¹,

Tang²,

Chan³

et al. 2018

Oncotarget

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Our pilot short-term data suggested efficacy of sirolimus treatment in lupus nephritis (LN) patients, but its long-term data remains limited. We retrospectively reviewed 16 Class III/IV/V LN patients who have received prednisolone and sirolimus either as initial or maintenance treatment. Sixteen patients received sirolimus treatment (9 due to intolerance to standard immunosuppressants and 7 due to a history of malignancy) for 45.3 ± 36.5 months. In five patients sirolimus and prednisolone was given as induction for active nephritis, and they showed improvements in proteinuria (2.8 ± 1.9 g/day at baseline, 0.1 ± 0.1 g/day after 36 months, p = 0.011), anti-dsDNA (107.7 ± 91.9 IU/mL and 37.0 ± 55.4 IU/mL respectively, p = 0.178) and C3 (54.8 ± 26.1 mg/dL and 86.3 ± 18.6 mg/dL respectively, p = 0.081). Eleven patients received sirolimus and low-dose prednisolone as long-term maintenance, and they showed continued improvement in C3 (90.4 ± 18.1 mg/dL and 117.7±25.1 mg/dL at commencement and after 36 months respectively, p = 0.025) and stable renal function (eGFR 58.6 ± 25.8 ml/min and 63.0 ± 29.6 mL/min respectively, p = 0.239) and proteinuria (0.8 ± 0.7 g/day and 0.7 ± 0.7 g/day respectively, p = 0.252). Renal flare occurred in one patient and another patient with Stage 4 chronic kidney disease when sirolimus was started developed endstage renal failure after 27 months. Sirolimus was discontinued in five patients, in four cases related to drug sideeffects. Deterioration of dyslipidaemia occurred in four patients, but was adequately controlled with statin therapy. The preliminary evidence suggests that sirolimus may serve as an alternative treatment for LN who do not tolerate standard treatment or had history of malignancy, and with acceptable long-term safety profile.

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Section: Adverse Eventsmentioning

confidence: 99%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

Yap¹,

Tang²,

Chan³

et al. 2018

Oncotarget

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“…Rapamycin prolonged survival, normalized proteinuria, and reduced anti-dsDNA titers in lupus-prone mice, while ameliorating histological lesions and Akt/mTOR glomerular expression [49]. Mechanistic studies have uncovered multiple distinct mechanisms of action of rapamycin in SLE that are mediated by inhibition of mTORC1, including the suppression of IL17 expression by CD4+T cells and the expansion of Tregs [46].…”

Section: Oxidative Stress In Sle T Cellsmentioning

confidence: 99%

T Cell Targeted Therapies in Lupus: Do They Make Sense?

Thanou

Merrill

2015

Curr Treat Options in Rheum

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“…Furthermore, MGD10103 increased NF-κB activation and resulted in increased TNF-α expression and production [80]. For these reasons, MGCD0103 may not be optimal for treatment for autoimmune diseases, including SLE and RA, which are characterized by increased PI3K/AKT/mTOR signaling and NF-κB activation [83][84][85].…”

Section: Selective Class I Inhibitorsmentioning

confidence: 99%

Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

Regna

Reilly²

2014

J Clin Cell Immunol

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Histone deacetylases are a class of enzymes that play an important role in protein modification and cellular function. Ongoing research suggests that HDAC inhibitors may be efficacious in the treatment of a wide range of diseases from cancer to autoimmune disease. HDACi therapy has shown promising results both in vitro and in vivo for the treatment of autoimmune disease. To date, 18 isoforms of HDACs have been identified, which exist in four different classes: class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10) class III (sirtuins1-7), and class IV (HDAC11). The mechanism of action through which HDACs function remains to be fully elucidated. However, the use of isoform-selective HDAC inhibitors has been helpful in determining the physiological role of individual HDACs as well as in decreasing the toxicity of HDACi therapy. This review will focus on isoform-selective HDACs and how they may be effective for the treatment of autoimmune disease.

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The PI3K/Akt/mTOR pathway is activated in murine lupus nephritis and downregulated by rapamycin

Cited by 94 publications

References 46 publications

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

T Cell Targeted Therapies in Lupus: Do They Make Sense?

Isoform-Selective HDAC Inhibition in Autoimmune DiseaseNicole L Regna1* and Christopher M Reilly2

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