Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice

Stylianou, Kostas; Petrakis, Ioannis; Mavroeidi, Vasiliki; Stratakis, Stavros; Kokologiannakis, George; Lioudaki, Eirini; Liotsi, Christina; Kroustalakis, Nikos; Vardaki, Eleftheria; Stratigis, Spyros; Perakis, Kostas; Kyriazis, John; Nakopoulou, Lydia; Daphnis, Eugene

doi:10.1093/ndt/gfr791

Cited by 11 publications

(10 citation statements)

References 45 publications

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“…[22]. However, data from kidney transplant recipients suggested that mTOR inhibitors might induce proteinuria due to their action on glomerular podocytes and renal tubular cells, and significant increase in proteinuria after mTOR inhibitor treatment was associated with inferior renal allograft outcome [23][24][25][26]. Our data shows that in patients given prednisolone and sirolimus for the treatment of active LN, their proteinuria decreased while renal function improved.…”

Section: Adverse Eventsmentioning

confidence: 61%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis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: 61%

WITHDRAWN: Long-term data on sirolimus treatment in patients with lupus nephritis

Yap¹,

Tang²,

Chan³

et al. 2018

Oncotarget

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“…However, in some cases, rapamycin has proven to be harmful. Rapamycin-induced renal injury in healthy mice, which was accompanied by an increased mean podocyte foot process width, and reduced the levels of nephrin and podocin proteins [31]. The contrasting actions of rapamycin on experimental renal disease have also been observed in patients.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Induces Autophagy and Reduces the Apoptosis of Podocytes Under a Stimulated Condition of Immunoglobulin A Nephropathy

Liang¹,

Jin²,

Lin³

et al. 2017

Kidney Blood Press Res

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Backgroud/Aims: The aim of this study was to investigate the potential renoprotective effect of rapamycin on the autophagy of podocytes treated with the supernatant of mesangial cells cultured with aggregated IgA1 (aIgA1) from immunoglobulin A nephropathy (IgAN) patients. Methods: Monomeric IgA1 (mIgA1) was isolated from the serum of IgAN patients or healthy volunteers, and then transformed to aIgA1 by heating. Subsequently, the aIgA1-mesangial cell supernatant was prepared by collecting the medium of mouse mesangial cells (MSC1097) cultured with aIgA1 (100 mg/L) from different IgAN patients or healthy volunteers for 48 h. Subsequently mouse podocytes (MPC5) were exposed to the supernatant of the aIgA1-mesangial cells for 24 h, using 100 mg/L aIgA1 from healthy volunteers as the control group or 100 mg/L aIgA1 from IgAN patients as the IgANs group, in RPMI 1640 medium. The MPC5 cells in the IgANs+Rap group were cultured with rapamycin (10 nmol/L) and the supernatant of MSC-1097 cells cultured with aIgA1 from IgAN patients in RPMI 1640 medium. Autophagy was assessed by western blot analysis (LC3, p62), electron microscopy, and immunofluorescence staining (LC3, p62, and CD63). The apoptosis of podocytes was evaluated by flow cytometry, and the expression of apoptosis-associated proteins cleaved-caspase-3 and caspase-3 were determined by western blot analysis. Results: Deficient autophagy, which was evident by decreased LC3-II and CD63 levels, caused accumulation of p62, and fewer autophagosomes were observed in the MPC5 cells cultured with the IgAN supernatant, along with stronger expression of cleaved caspase-3 and a higher apoptosis rate. Inhibition of autophagy was alleviated in the IgANs+Rap group. The LC3-II/LC3-I ratio increased by almost 30%, the accumulated p62 amount was reduced by 50%, and the number of autophagosomes per podocyte increased to about 7 times that of the IgAN groups. These results were confirmed by immunofluorescence staining. In addition, the apoptosis rate of MPC5 cells decreased from 19.88% in the IgAN group to 16.78% in the IgANs+Rap group, which was accompanied by a weaker expression level of cleaved caspase-3. Conclusions: Rapamycin can reduce the apoptosis of podocytes by inducing autophagy in IgAN.

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“…In contrast to previously published work, high-dose rapamycin treatment also exerted positive effects on halting the development of FSGS-like lesions in our ADR model, suggesting that the potential podocyte-toxic effects of higher doses of rapamycin vary depending on the mouse background, the pharmacodynamics, and the dose of ADR. 44 Nonetheless, there is need for further studies to define the subpopulation of human patients with FSGS who may benefit from pharmacologic inhibition of mTORC1, as well as the dose dependency of renal adverse events.…”

Section: Partial Mtor Inhibition As a Novel Therapeutic Concept To Trmentioning

confidence: 99%

Targeting mTOR Signaling Can Prevent the Progression of FSGS

Zschiedrich

Bork

Liang

et al. 2017

JASN

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Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both alleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just one allele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatment with the mTORC1 inhibitor rapamycin efficiently diminished disease progression. Mechanistically, complete pharmacologic inhibition of mTOR in immortalized podocytes shifted the cellular energy metabolism toward reduced rates of oxidative phosphorylation and anaerobic glycolysis, which correlated with increased production of reactive oxygen species. Together, these data suggest that podocyte injury and loss is commonly followed by adaptive mTOR activation. Prolonged mTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition.

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Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice

Abstract: Rapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period.

Cited by 11 publications

References 45 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

Rapamycin Induces Autophagy and Reduces the Apoptosis of Podocytes Under a Stimulated Condition of Immunoglobulin A Nephropathy

Targeting mTOR Signaling Can Prevent the Progression of FSGS

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