Journal
CELL DEATH & DISEASE
Volume 12, Issue 3, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03460-x
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Funding
- National Natural Science Foundation of China [81970633, 81670663]
- Henan Joint Funds of the National Natural Science Foundation of China (Key Support Projects) [U1604284]
- National Key Research and Development Program [2016YFC1305404]
- Comprehensive and digital demonstration platform for clinical evaluation technology of new drugs for major diseases [2020ZX09201-009]
- Provincial and ministerial co-construction project of Henan [SB201901015]
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This study found that miR-483-5p is decreased in kidney tissues of diabetic mice and in tubular epithelial cells stimulated with high glucose, but increased in exosomes derived from diabetic mouse kidney tissues. miR-483-5p inhibits fibrosis-related gene expressions by binding to TIMP2 and MAPK1, thus alleviating the progression of DN-induced renal interstitial fibrosis.
Diabetic nephropathy (DN) is a serious complication in type 1 and type 2 diabetes, and renal interstitial fibrosis plays a key role in DN progression. Here, we aimed to probe into the role and potential mechanism of miR-483-5p in DN-induced renal interstitial fibrosis. In this study, we corroborated that miR-483-5p expression was lessened in type 1 and type 2 diabetic mice kidney tissues and high glucose (HG)-stimulated tubular epithelial cells (TECs), and raised in the exosomes derived from renal tissues in type 1 and type 2 diabetic mice. miR-483-5p restrained the expressions of fibrosis-related genes in vitro and renal interstitial fibrosis in vivo. Mechanistically, miR-483-5p bound both TIMP2 and MAPK1, and TIMP2 and MAPK1 were bound up with the regulation of miR-483-5p on renal TECs under HG conditions. Importantly, HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine. Our results expounded that HNRNPA1-mediated exosomal sorting transported cellular miR-483-5p out of TECs into the urine, thus lessening the restraint of cellular miR-483-5p on MAPK1 and TIMP2 mRNAs, and ultimately boosting extracellular matrix deposition and the progression of DN-induced renal interstitial fibrosis.
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