Intermittent Hypoxia Up-Regulates CCL2, RETN, and TNFα mRNAs in Adipocytes via Down-regulation of miR-452

Sleep apnea syndrome (SAS), characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for insulin resistance. Recently, IH is considered to independently cause adipose tissue inflammation/dysfunction, leading to worsening insulin resistance; however, the detailed mechanism remains unknown. We exposed mouse 3T3-L1 and human SW872 adipocytes to experimental IH or normoxia for 24 h, and analyzed mRNA expression of several adipokines. We found that the mRNA levels of RETN, TNFα, and CCL2 in SW872 and 3T3-L1 adipocytes were significantly increased by IH, whereas the promoter activities of these genes were not increased. A target mRNA search of microRNA (miR)s revealed that all human mRNAs have a potential target sequence for miR-452. The miR-452 level of IH-treated cells was significantly decreased compared to normoxia-treated cells. MiR-452 mimic and non-specific control RNA (miR-452 mimic NC) were introduced into SW872 cells, and the IH-induced up-regulation of the genes was abolished by introduction of the miR-452 mimic but not by the miR-452 mimic NC. These results indicate that IH stress down-regulates the miR-452 in adipocytes, resulting in increased levels of RETN, TNFα, and CCL2 mRNAs, leading to insulin resistance in SAS patients.

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Intermittent Hypoxia Upregulates the Renin and Cd38 mRNAs in Renin-Producing Cells via the Downregulation of miR-203

International Journal of Molecular Sciences ◽

10.3390/ijms221810127 ◽

2021 ◽

Vol 22 (18) ◽

pp. 10127

Author(s):

Yoshinori Takeda ◽

Asako Itaya-Hironaka ◽

Akiyo Yamauchi ◽

Mai Makino ◽

Sumiyo Sakuramoto-Tsuchida ◽

...

Keyword(s):

Intermittent Hypoxia ◽

Sleep Apnea Syndrome ◽

Renin Angiotensin System ◽

Negative Control ◽

Target Sequence ◽

Mrna Levels ◽

Chain Reaction ◽

Angiotensin System ◽

Cyclic Adp Ribose ◽

Polymerase Chain

Sleep apnea syndrome is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), and it is a known risk factor for hypertension. The upregulation of the renin-angiotensin system has been reported in IH, and the correlation between renin and CD38 has been noted. We exposed human HEK293 and mouse As4.1 renal cells to experimental IH or normoxia for 24 h and then measured the mRNA levels using a real-time reverse transcription polymerase chain reaction. The mRNA levels of Renin (Ren) and Cd38 were significantly increased by IH, indicating that they could be involved in the CD38-cyclic ADP-ribose signaling pathway. We next investigated the promotor activities of both genes, which were not increased by IH. Yet, a target mRNA search of the microRNA (miRNA) revealed both mRNAs to have a potential target sequence for miR-203. The miR-203 level of the IH-treated cells was significantly decreased when compared with the normoxia-treated cells. The IH-induced upregulation of the genes was abolished by the introduction of the miR-203 mimic, but not the miR-203 mimic NC negative control. These results indicate that IH stress downregulates the miR-203 in renin-producing cells, thereby resulting in increased mRNA levels of Ren and Cd38, which leads to hypertension.

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Relationship Between Intermittent Hypoxia and Type 2 Diabetes in Sleep Apnea Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms20194756 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4756 ◽

Cited By ~ 4

Author(s):

Hiroyo Ota ◽

Yukio Fujita ◽

Motoo Yamauchi ◽

Shigeo Muro ◽

Hiroshi Kimura ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Sleep Apnea ◽

Intermittent Hypoxia ◽

Sleep Apnea Syndrome ◽

Common Disease ◽

Peripheral Tissues ◽

Cellular Models ◽

Apnea Syndrome

Sleep apnea syndrome (SAS) is a very common disease involving intermittent hypoxia (IH), recurrent symptoms of deoxygenation during sleep, strong daytime sleepiness, and significant loss of quality of life. A number of epidemiological researches have shown that SAS is an important risk factor for insulin resistance and type 2 diabetes mellitus (DM), which is associated with SAS regardless of age, gender, or body habitus. IH, hallmark of SAS, plays an important role in the pathogenesis of SAS and experimental studies with animal and cellular models indicate that IH leads to attenuation of glucose-induced insulin secretion from pancreatic β cells and to enhancement of insulin resistance in peripheral tissues and cells, such as liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes). In this review, we focus on IH-induced dysfunction in glucose metabolism and its underlying molecular mechanisms in several cells and tissues related to glucose homeostasis.

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