miR-21–Containing Microvesicles from Injured Tubular Epithelial Cells Promote Tubular Phenotype Transition by Targeting PTEN Protein

• DOI: 10.1016/j.ajpath.2013.06.032
• Publication Date: 2013-08-23T22:02:16Z
• Authors: Yang Zhou; Mingxia Xiong; Li Fang; Lei Jiang; Ping Wen; Chunsun Dai; Chen-yu Zhang; Junwei Yang
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Cytoplasmic Vesicles; PTEN Phosphohydrolase; Epithelial Cells; Models, Biological; Matrix Metalloproteinases; Cell Line; Rats; Up-Regulation; Transforming Growth Factor beta1; Mice; MicroRNAs; 03 medical and health sciences; Kidney Tubules; Phenotype; Culture Media, Conditioned; Animals; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

Renal fibrosis is inevitably progressive no matter what the initial insult is or whether the insult persists. In an experimental fibrosis model induced by unilateral ureteral obstruction, the accelerated pathological changes could hardly be explained by aggravated pressure caused by hydronephrosis after ligation. Moreover, at the initial stage, tubular phenotype transition and matrix deposition in obstructive kidneys are always local and scattered; however, these renal lesions expand and progress with time. In this study, cultured recipient tubular cells underwent phenotype transition after incubation with conditioned media derived from transforming growth factor-β1-treated donor tubular cells. Thus, it is reasonable to speculate that some secretable molecules from injured tubules contribute to the progression of renal fibrosis. Herein, we report that secreted miRNA-21 (miR-21) can serve as the molecule mediating intercellular communication. miR-21 was packaged into microvesicles, which enter and deliver miR-21 into recipient tubular cells, and exogenous miR-21 enhances Akt signaling by target depression of phosphatase and tensin homolog (PTEN) protein, and promotes tubular phenotype transition. These results demonstrate that tubular cells can secrete miR-21 and deliver it into recipient tubules by microvesicles, where the exogenous miR-21 can target PTEN protein and enhance Akt signaling in recipient cells. Microvesicle-mediated delivery of miR-21 among tubular epithelial cells might shed new light on the mechanism of progressive renal fibrosis.