期刊
FASEB JOURNAL
卷 29, 期 2, 页码 540-553出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-254789
关键词
interstitial kidney injury; macrophage infiltration; transforming growth factor-beta; myofibroblast differentiation; collagen deposition; matrix metalloproteinase
Chronic kidney disease (CKD) results from the development of fibrosis, ultimately leading to endstage renal disease (ESRD). Although human bone marrow-derived mesenchymal stem cells (MSCs) can accelerate renal repair following acute injury, the establishment of fibrosis during CKD may affect their potential to influence regeneration capacity. Here we tested the novel combination of MSCs with the antifibrotic serelaxin to repair and protect the kidney 7 d post-unilateral ureteral obstruction (UUO), when fibrosis is established. Male C57BL6 mice were sham-operated or UUO-inured (n = 4-6) and received vehicle, MSCs (1 3 106), serelaxin (0.5 mg/ kg per d), or the combination of both. In vivo tracing studies with luciferin/ enhanced green fluorescent protein (eGFP)-taggedMSCs showed specific localization in the obstructed kidney where they remained for 36 h. Combination therapy conferred significant protection from UUO-induced fibrosis, as indicated by hydroxyproline analysis (P < 0.001 vs. vehicle, P < 0.05 vs. MSC or serelaxin alone). This was accompanied by preserved structural architecture, decreased tubular epithelial injury (P < 0.01 vs. MSCs alone), macrophage infiltration, and myofibroblast localization in the kidney (both P < 0.01 vs. vehicle). Combination therapy also stimulated matrix metalloproteinase (MMP)-2 activity over either treatment alone (P < 0.05 vs. either treatment alone). These results suggest that the presence of an antifibrotic in conjunction with MSCsameliorates established kidneyfibrosis and augments tissue repair to a greater extent than either treatment alone.-
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