Rapamycin Slows IgA Nephropathy Progression in the Rat

Tian, Jing; Wang, Yanhong; Zhou, Xiaoshuang; Li, Yanjiao; Wang, Chen; Li, Jiaming; Li, Rongshan

doi:10.1159/000358844

Cited by 21 publications

(12 citation statements)

References 34 publications

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“…As no ddY mouse was available in China, we used the animal IgAN model in which a direct antigenic stimulus to esophageal endothelial mucosal cells activates local and migratory macrophages was based on our previous studies [28] . Data from other studies have also shown that this method can build a good stable animal model for IgAN [29,30] . IgAN was induced by continuous oral immunization with 0.1% BSA (G7516, Sigma Chemical Co., St. Louis, Mo., USA) with 6 m M HCl in tap water for 10 weeks, followed by tail intravenous injection of 1 mg BSA daily for 3 successive days.…”

Section: Animals and Experimental Designmentioning

confidence: 78%

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

He¹,

Peng²,

Wang³

et al. 2015

Am J Nephrol

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Background: Immunoglobulin class-switch recombination (CSR) is crucial for the expression of IgA, and it plays a vital role in the physiopathology of IgA nephropathy (IgAN). The aim of the study is to investigate the effect of polyriboinosinic:polyribocytidylic acid (poly(I:C)) in modulating toll-like receptor (TLR) 3-B-cell-activating factor belonging to the TNF family (BAFF) axis activation, which in turn promotes IgA CSR of IgAN patients and the IgAN rat model. Methods: Blood samples and tonsillar tissue specimens were obtained from 24 patients with IgAN and 26 patients with chronic tonsillitis as control. We also used the IgAN rat model to investigate the relationship between viral infection and IgA CSR. Results: Immunohistochemical and ELISA western blotting examination revealed that the TLR3/BAFF axis is activated in IgAN patients when compared to controls. Synthetic double-stranded RNA poly(I:C) stimulation upregulates the TACI/TLR3/TRIF/TRAF6 expression and promotes IgA CSR and BAFF productions in tonsil mononuclear cells. TLR3 or BAFF siRNA decreases IgA expression. In IgAN rat models, TLR3/BAFF signaling was highly activated. With 200 μg poly(I:C) sodium salt into the left naris for 8 weeks, IgA was highly deposited on glomeruli. It also revealed that poly(I:C) activated TLR3/BAFF axis and IgA CSR in vivo. Conclusion: These data points toward the role of TLR3/BAFF axis in IgA CSR of IgAN, and the data also support the notion that mucosal immunization with virus infection results in impaired mucosal and systemic IgA responses.

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Section: Animals and Experimental Designmentioning

confidence: 78%

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

He¹,

Peng²,

Wang³

et al. 2015

Am J Nephrol

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“…It was reported that the early application of the low-dose mTOR inhibitor rapamycin, at 1 mg·kg -1 ·day -1 for 6 weeks, may slow the progression of IgAN-induced renal injury in rats [24]. 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].…”

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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“…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 Slows IgA Nephropathy Progression in the Rat

Cited by 21 publications

References 34 publications

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

Synthetic Double-Stranded RNA Poly(I:C) Aggravates IgA Nephropathy by Triggering IgA Class Switching Recombination through the TLR3-BAFF Axis

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

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

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