期刊
DIABETES
卷 70, 期 7, 页码 1536-1548出版社
AMER DIABETES ASSOC
DOI: 10.2337/db20-1108
关键词
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资金
- U.S. Department of Veterans Affairs (Merit Review Award) [I01 BX000319]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK058831, DK087843]
- Senior Research Career Scientist award from the U.S. Department of Veterans Affairs
In diabetic kidney disease, FOXO1 phosphorylation leads to downregulation of RAB27B, resulting in decreased exosome secretion.
Exosomes have been implicated in diabetic kidney disease (DKD), but the regulation of exosomes in DKD is largely unknown. Here, we have verified the decrease of exosome secretion in DKD and unveiled the underlying mechanism. In Boston University mouse proximal tubule (BUMPT) cells, high-glucose (HG) treatment led to a significant decrease in exosome secretion, which was associated with specific downregulation of RAB27B, a key guanosine-5 '-triphosphatase in exosome secretion. Overexpression of RAB27B restored exosome secretion in HG-treated cells, suggesting a role of RAB27B downregulation in the decrease of exosome secretion in DKD. To understand the mechanism of RAB27B downregulation, we conducted bioinformatics analysis that identified FOXO1 binding sites in the Rab27b gene promoter. Consistently, HG induced phosphorylation of FOXO1 in BUMPT cells, preventing FOXO1 accumulation and activation in the nucleus. Overexpression of nonphosphorylatable, constitutively active FOXO1 led to the upregulation of RAB27B and an increase in exosome secretion in HG-treated cells. In vivo, compared with normal mice, diabetic mice showed increased FOXO1 phosphorylation, decreased RAB27B expression, and reduced exosome secretion. Collectively, these results unveil the mechanism of exosome dysfunction in DKD where FOXO1 is phosphorylated and inactivated in DKD, resulting in RAB27B downregulation and the decrease of exosome secretion.
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