Roles of mTOR in Diabetic Kidney Disease

Yasuda‐Yamahara, Mako; Kume, Shinji; Maegawa, Hiroshi

doi:10.3390/antiox10020321

Cited by 28 publications

(34 citation statements)

References 74 publications

(44 reference statements)

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“…RAPA/MET‐treatment prevented the advancement of MET‐driven glomerulonephritis, development of hyaline thrombi, and the elevation of ACR that was generated by MET‐treatment alone (Figure 5 ). In diabetic kidney disease, hyperactivated mTORC1 may be involved in the pathogenesis of podocyte and tubular cell injury (Yasuda‐Yamahara et al, 2021 ). Suppression of diabetic nephropathy by direct inhibition of mTORC1 in the podocyte of the nephron (Inoki et al, 2011 ) provides a direct mechanism for the RAPA‐mediated protection.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

et al. 2022

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Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/ LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA-IR, and inflammation, and prevented hyperinsulinemia and pre-steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c-reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulinresistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin-induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of "insulin signaling restriction" that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the

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Section: Discussionmentioning

confidence: 99%

Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

et al. 2022

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“…In cancer, diabetes and other diseases characterized by abnormal glucose metabolism, mTORC1 is deregulated [195,197]. In diabetes, hyperactivated mTORC1 is involved in the pathogenesis of cardiomyopathy [198], diabetic retinopathy [199] and diabetic kidney disease [200]. Unfortunately, the role of mTORC1 signaling in GV-related vascular effects has not been studied to date.…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Glucose Variability: How Does It Work?

Климонтов

Saik

Korbut

2021

IJMS

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A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.

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“…Removal of impaired or dysfunctional mitochondria is also a possible approach. mTOR inhibitors promote autophagy and remove impaired mitochondria, but may also inhibit cell proliferation, making clinical application difficult [87]. Furthermore, chronic use of mTOR inhibitors may contribute to glucose intolerance and lead to dysfunction of the kidneys.…”

Section: Oxidative Stress As a Therapeutic Targetmentioning

confidence: 99%

Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

2021

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Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

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Roles of mTOR in Diabetic Kidney Disease

Cited by 28 publications

References 74 publications

Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

Glucose Variability: How Does It Work?

Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

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