Combination therapy of mesenchymal stem cells and serelaxin effectively attenuates renal fibrosis in obstructive nephropathy

被引:66
作者
Huuskes, Brooke M. [1 ]
Wise, Andrea F. [1 ]
Cox, Alison J. [3 ]
Lim, Ee X. [1 ]
Payne, Natalie L. [4 ]
Kelly, Darren J. [3 ]
Samuel, Chrishan S. [2 ]
Ricardo, Sharon D. [1 ]
机构
[1] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia
[2] Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia
[3] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic, Australia
[4] Monash Univ, ARMI, Clayton, Vic 3800, Australia
关键词
interstitial kidney injury; macrophage infiltration; transforming growth factor-beta; myofibroblast differentiation; collagen deposition; matrix metalloproteinase; ACUTE KIDNEY INJURY; UNILATERAL URETERAL OBSTRUCTION; ISCHEMIA-REPERFUSION INJURY; STROMAL CELLS; TUBULOINTERSTITIAL FIBROSIS; INTERSTITIAL FIBROSIS; MATRIX METALLOPROTEINASES; MOLECULE-1; EXPRESSION; MYOCARDIAL-INFARCTION; RELAXIN DECREASES;
D O I
10.1096/fj.14-254789
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.-
引用
收藏
页码:540 / 553
页数:14
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