Renal mTORC1 activation is associated with disease activity and prognosis in lupus nephritis

Mao, Zhizhong; Tan, Ying; Tao, Juan; Li, Linlin; Huī, Wánɡ; Feng, Yu; Perl, András; Zhao, Ming‐Hui

doi:10.1093/rheumatology/keac037

Cited by 30 publications

(33 citation statements)

References 39 publications

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“…89 mTOR-activating sequence variations can cause clinical cardiomyopathy and kidney tubulopathy 90 and renal mTORC1 activation is associated with disease activity and prognosis in patients with nondiabetic kidney disease. 91 Sirtuin 1 and Other Sirtuins Sirtuins are a family of redox-sensitive nicotinamide adenine dinucleotide (NAD)-dependent deacetylases that catalyze the posttranslational modification of hundreds of proteins that are involved in metabolism and cellular homeostasis. They serve as a redox rheostat and represent the primary cellular response to glucose deprivation.…”

Section: Mammalian Target Of Rapamycinmentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

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Section: Mammalian Target Of Rapamycinmentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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“…Treatment with rapamycin improved the immune response and function, and reduced the proportion of Th1, Th2, Th17, and DN T cells in the spleen, kidney, and peripheral blood [33,45,55]; 4) Treatment with rapamycin blocked the IL-4 production and necrosis of DN T cells, which can release immunogenic nuclear materials [56]; 5) Rapamycin reduced intrarenal CCL5 expression and decreased CD4 + , CD8 + T cell, B cell, and macrophage infiltration in the kidneys [32]; 6) Rapamycin reverses the senescent pheno-type and improves immune regulation of mesenchymal stem cells from LN [57]; 7) mTORC1 and mTORC2 are markedly activated, which may underlie the diminished autophagy in podocytes, mesangial cells, endothelial cells and tubular epithelial cells of LN patients. Autophagy is protective within podocytes and required for recovery from autoantibody-induced podocyte injury [54,58]. Maybe rapamycin treatment is renoprotective through promoting autophagy in podocytes, mesangial cells, endothelial cells and tubular epithelial cells; 8) Rapamycin decreased mesangial cell proliferation, and their binding with anti-PBS RAPA dsDNA antibodies.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model

Gao¹,

Fan²,

Li³

et al. 2022

cejoi

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Lupus nephritis (Ln) is a severe consequence of systemic lupus erythematosus (sLE) and is an important driver of morbidity and mortality in sLE. Treg cells and TiM-3 play an important role in the pathogenesis of Ln. The beneficial effect of rapamycin on Ln has been confirmed in both mouse models and patients, but the effect of rapamycin on Treg cells and TiM-3 is not yet completely understood. in this study, rapamycin treatment attenuated proteinuria, histological damage, and renal deposition of C3, and improved renal function. spleen and renal draining lymph node weight and serum levels of anti-dsDna antibodies were also improved by rapamycin. furthermore, the frequency of Treg cells and Treg functional molecules, such as cytotoxic T cell antigen 4 (CTLa-4), interleukin 10 (iL-10), and transforming growth factor β1 (Tgf-β1), increased significantly after treatment with rapamycin in MRL/lpr mice. We also found that expression of TiM-3 was significantly decreased in CD4+ T cells and Treg cells in mice treated with rapamycin. in summary, the study demonstrated that rapamycin treatment induced preferential expansion of CD4+CD25+foxp3+ Tregs with increased expression of , and decreased TiM-3 expression, thereby ameliorating lupus nephritis in the MRL/lpr mouse model.

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“…Furthermore, in a recent clinical trial in active symptomatic SLE participants, 12 months of sirolimus treatment was associated with improvement in disease activity, which was suggested to be associated with modification of inflammatory T-cell lineage specification ( Lai et al, 2018 ). In addition to these findings, it has recently been shown that mTORC1 activation in glomeruli is higher in participants with lupus nephritis than in participants with DMN ( Mao et al, 2022 ), that ATG5 and ATG7 and the HRES-1/Rab4A are associated with the molecular pathogenesis of lupus, and genetically driven mTOR activation is associated with fulminant lupus nephritis ( Caza et al, 2022 ).…”

Section: Mtor and Inflammationmentioning

confidence: 94%

Insulin-induced mTOR signaling and gluconeogenesis in renal proximal tubules: A mini-review of current evidence and therapeutic potential

et al. 2022

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Energy is continuously expended in the body, and gluconeogenesis maintains glucose homeostasis during starvation. Gluconeogenesis occurs in the liver and kidneys. The proximal tubule is the primary location for renal gluconeogenesis, accounting for up to 25% and 60% of endogenous glucose production during fasting and after a meal, respectively. The mechanistic target of rapamycin (mTOR), which exists downstream of the insulin pathway, plays an important role in regulating proximal tubular gluconeogenesis. mTOR is an atypical serine/threonine kinase present in two complexes. mTORC1 phosphorylates substrates that enhance anabolic processes such as mRNA translation and lipid synthesis and catabolic processes such as autophagy. mTORC2 regulates cytoskeletal dynamics and controls ion transport and proliferation via phosphorylation of SGK1. Therefore, mTOR signaling defects have been implicated in various pathological conditions, including cancer, cardiovascular disease, and diabetes. However, concrete elucidations of the associated mechanisms are still unclear. This review provides an overview of mTOR and describes the relationship between mTOR and renal.

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Renal mTORC1 activation is associated with disease activity and prognosis in lupus nephritis

Cited by 30 publications

References 39 publications

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Rapamycin relieves lupus nephritis by regulating TIM-3 and CD4+CD25+Foxp3+ Treg cells in an MRL/lpr mouse model

Insulin-induced mTOR signaling and gluconeogenesis in renal proximal tubules: A mini-review of current evidence and therapeutic potential

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