Atorvastatin improves survival of implanted stem cells in a rat model of renal ischemia-reperfusion injury.
OBJECTIVE
To investigate the impacts of combinatorial atorvastatin (Ator) perioperative administration and mesenchymal stem cell (MSC) implantation on therapeutic effects in the rat experimental acute kidney injury.


METHODS
The model of renal ischemia-reperfusion (I/R) injury was induced by the release of bilateral renal pedicle clamps following 45 min of occlusion. Immediately after reperfusion, CM-Dil-labeled MSCs (1 × 10(6) cells) or vehicles only were administered through the carotid artery of the animals pretreated with or without Ator.


RESULTS
The combined treatment with Ator and MSCs (Ator+MSCs) markedly reduced the elevated levels of serum creatinine and blood urea nitrogen, as well as the severity of renal damage 24 h after I/R injury. In addition, we also observed inhibition of renal tubular cell apoptosis and promotion of proliferation in the Ator+MSCs group compared with the other groups. Consistent with the improvement in renal function and morphology, Ator pretreatment significantly ameliorated oxidative stress, inhibited inflammation response, and increased the viability of implanted MSCs. With regard to the further mechanism, we found that the expression of Toll-like receptor 4 (TLR4) and high-mobility group box 1, potential mediators of innate immunity, was significantly decreased in the Ator-treated groups.


CONCLUSIONS
Ator treatment may protect the kidney undergoing I/R injury through suppression of TLR4 signaling, creating a better environment for the survival of grafted MSCs. The extra benefit of the Ator+MSCs combined therapy may result from the Ator-mediated inhibition of oxidative stress and inflammation in the ischemic kidney.
Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Jieru
J
Cai
Xiaofang
X
Yu
Bingying
B
Zhang
Hui
H
Zhang
Yi
Y
Fang
Shaopeng
S
Liu
Tongqiang
T
Liu
Xiaoqiang
X
Ding
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D000069059:Atorvastatin; D006085:Graft Survival / Q000187:drug effects*; D024243:HMGB1 Protein / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000187:drug effects
D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000069059:Atorvastatin