Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms

Tian, Jing; Wang, Yanhong; Li, Xinyan; Zhou, Xiaoshuang; Li, Rongshan

doi:10.1177/1535370214555666

Cited by 17 publications

(16 citation statements)

References 37 publications

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“…The underlying mechanism for the beneficial effect of rapamycin on IgAN is likely to be cell cycle-dependent, because rapamycin inhibited mesangial cell proliferation and arrested the cell cycle in the G1 phase, without affecting the expression of cyclin E and cyclin-dependent kinase [25]. In fact, the same authors found that the Akt/mTOR/p70S6K pathway was activated in the renal cortex of rats with IgAN.…”

Section: Discussionmentioning

confidence: 79%

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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Section: Discussionmentioning

confidence: 79%

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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“… 23 It was reported that a low dose of the mTOR inhibitor rapamycin can inhibit mesangial cell proliferation and slow the progression of renal fibrosis of IgAN by modulating the cell cycle regulatory proteins and blocking the G1-to-S transition. 24 Tamouza et al found that the MAPK/ERK pathway was activated in mesangial areas of IgAN patients with proteinuria (>1 g/day) and elevated blood pressure, which could alter the cross-talk between mesangial cells and podocytes and thus generate renal dysfunction in IgAN. What is more, as IgA1-dependent MAPK/ERK activation requires RAS activity, using RAS blocker therapy can more effectively mitigate proteinuria in IgAN patients with a high mesangial score for MAPK/ERK activation.…”

Section: Discussionmentioning

confidence: 99%

The mTOR/p70S6K1 signaling pathway in renal fibrosis of children with immunoglobulin A nephropathy

Ling

Yang

et al. 2017

J Renin Angiotensin Aldosterone Syst

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Aim:The purpose of this study was to explore whether mTOR/p70S6K1 signaling is activated in renal fibrosis of immunoglobulin A nephropathy.Methods:Seventy-two children with immunoglobulin A nephropathy were divided into three groups according to their clinical features and pathological grades. Six normal renal specimens were included in the control group. The expression levels of angiotensin II, mTOR, p70S6K1, E-cadherin, and α-smooth muscle actin in renal tissues were determined by immunohistochemistry method, the potential correlations of these indexes and relationship between these indexes and the clinicopathological indexes were analyzed.Results:Compared to the control group, the expression levels of angiotensin II, mTOR, p70S6K1, and α-smooth muscle actin were significantly higher and the expression levels of E-cadherin were lower both in glomeruli and tubulointerstitium of immunoglobulin A nephropathy children. And the most significant differences were found in the nephrotic syndrome group and pathological grade IV group. In immunoglobulin A nephropathy renal tissues, the expression levels of angiotensin II in glomeruli and tubulointerstitium were both positively correlated with the expression levels of mTOR and α- smooth muscle actin, and negatively correlated with the expression levels of E-cadherin.Conclusion:The mTOR/p70S6K1 signaling was activated in renal tissues of children with immunoglobulin A nephropathy, and future studies will need to address the mechanism of mTOR/p70S6K1 signaling in the progress of renal fibrosis in immunoglobulin A nephropathy.

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“…Rapamycinn, as an mTOR inhibition, has been shown to progress slowly in several kidney injury models [17,18,19,20,21,22,23] As a frequently occuring immune-mediated kidney disease in Asia, IgAN, with a series of complex pathogenesis, was a research hotspot over the past few decades. But in IgAN, the role and the level of autophagy are unclear.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Enhances Repressed Autophagy and Attenuates Aggressive Progression in a Rat Model of IgA Nephropathy

Liu

Chen

et al. 2017

Am J Nephrol

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Background: IgA nephropathy (IgAN) has been considered to be the most frequent form of primary glomerulonephritis that occurs worldwide with a variety of factors involved in its occurrence and development. The impact of autophagy in IgAN, however, remains partially unclear. This study was designed to investigate the effects of rapamycin in an IgAN model. Method: After establishing an IgAN rat model, SD rats were divided into 4 groups: control, control + rapamycin, IgAN, IgAN + rapamycin. Proteinuria and the pathological changes and the level of autophagy of kidney were texted. Identify the expression of phosphorylation and total mammalian target of rapamycin (mTOR) and s6k1 as well as cyclin D1 in the kidney of rats through Western blot and immunohistochemistry. Results: With rapamycin treatment, we observed a significant reduction in the progression of proteinuria as well as alleviation of pathological lesions in IgAN rats. Besides, autophagy was inhibited, while the mTOR/S6k1 pathway was activated and expression of cyclin D1 was increased in IgAN. Rapamycin treatment increased autophagy and decreased the expression of cyclin D1. Conclusion: These results may suggest that mTOR-mediated autophagy inhibition may result in mesangial cell proliferation in IgAN.

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Rapamycin ameliorates IgA nephropathy via cell cycle-dependent mechanisms

Cited by 17 publications

References 37 publications

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

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

The mTOR/p70S6K1 signaling pathway in renal fibrosis of children with immunoglobulin A nephropathy

Rapamycin Enhances Repressed Autophagy and Attenuates Aggressive Progression in a Rat Model of IgA Nephropathy

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