Dataset Information

Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology.

ABSTRACT: Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes.

SUBMITTER: Shavlakadze T

PROVIDER: S-EPMC6001891 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology.

Shavlakadze Tea T Zhu Jiang J Wang Sharon S Zhou Weihua W Morin Bret B Egerman Marc A MA Fan Lin L Wang Yanqun Y Iartchouk Oleg O Meyer Angelika A Valdez Reginald A RA Mannick Joan B JB Klickstein Lloyd B LB Glass David J DJ

The journals of gerontology. Series A, Biological sciences and medical sciences 20180601 7

Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD00 ...[more]

PMID: 29304191

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Project description:Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH residues pose a particular risk to the kidneys and liver. However, the existence of biological effects with negative health implications at low environmentally relevant doses remains unresolved. A previous investigation addressed this issue, by conducting a 2-year feeding study, which included 10 female Sprague Dawley rats administered via drinking water with 0.1 ppb of a major Roundup formulation (50 ng/L glyphosate equivalent dilution). Hepatorenal toxicities, as well as urine and blood biochemistry disturbances at the 15th month of age were observed. In an effort to obtain molecular mechanistic insight into the underlying causes of these pathologies, we have carried out a transcriptome microarray analysis of the liver and kidneys from these same animals. The expression of 4224 and 4447 genes were found to be disturbed respectively in liver and kidney (p<0.01, q<0.08, fold change >1.1). Among the 1319 genes whose expression was altered in both tissues, 3 functional categories were over-represented. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. The transcription factor networks that can account for these disruptions were centered on CREB1, ESR1, YY1, c-Myc and Oct3/4 activity, which are known to closely cooperate in the regulation of gene expression after hormonal stimulation. The analysis of pathways and toxicity processes showed that these disturbances in gene expression were representative of fibrosis, necrosis, phospholipidosis, mitochondrial membrane dysfunction and ischemia, which correlate with the pathologies observed at an anatomical and histological level. Our results suggest that new studies incorporating testing principles from endocrinology and developmental epigenetics need to be performed to investigate potential consequences of exposure to low dose, environmental levels of GBH and glyphosate. Nine female rats were fed drinking water containing 0.1ppb Roundup formulation (50 ng/L glyphosate equivalent dilution). Ten control female rats were fed untreated drinking water. Samples of liver and kidney were taken for gene expression analysis.

Dataset Information

Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology.

Publications

Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology.

Similar Datasets

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