Atorvastatin Improves Survival of Implanted Stem Cells in a Rat Model of Renal Ischemia-Reperfusion Injury

Abstract

Aims: 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 × 10⁶ 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. Conclusion: 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.

Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury

“…The expression of IGF‐1 and VEGF genes also revealed many fold increases after preconditioning with SNAP . For drugs or health care products, Cai et al demonstrated that MSCs pretreated with atorvastatin expressed higher levels of IGF‐1, bFGF and HGF, similar to the results obtained by Mias et al, who incubated MSCs with melatonin . Liu et al used muscone to precondition MSCs, and higher levels of bone morphogenetic protein‐7 (BMP‐7) were observed both by real‐time qPCR and ELISA .…”

“…Cai et al pretreated MSCs with atorvastatin. They found that through suppression of TLR4 signalling, atorvastatin significantly increased the viability of implanted MSCs, consistent with the improvement in renal function and morphology . Melatonin, which was used as a dietary complement in humans, also presented potential to promote MSCs survival.…”

The orphan nuclear receptor RORα is a potential endogenous protector in renal ischemia/ reperfusion injury

“…The pathology assessment was performed as previously described in Cai et al . (17). Specifically, kidney tissue damage was classified based on the percentages of tubules with cell flattening and the degrees of tissue necrosis, brush border loss, and luminal cast formation.…”

“…RORα expression in the tissue sections was determined by immunohistochemical staining, as previously described in Cai et al (17), with anti–RORα (1:100; Abcam). RORα‐positive cell numbers were counted in 10 randomly chosen fields in the cortex or outer medulla of each section at ×400 magnification.…”

Effect of Pravastatin on Levels of Filtration Slit Diaphragm Protein and Oxidative Stress in Doxorubicin- Induced Nephrotoxicity

“…12 According to previous studies, statins can directly bind and metabolize reactive oxygen species resulting in reduction of intracellular reactive oxygen species content. 13,14 In the kidney, statins can prevent mitogen activated protein kinase and nuclear factor kappa B and also clear off free radicals. Moreover, they prevent the activation of signaling pathways through ROS.…”