Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration
Introduction
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease, with a significant increase in morbidity and mortality in patients with diabetes [1], [2], [3], [4]. Currently available treatments involving strict glycemic and/or blood pressure control can delay, but not eliminate the occurrence and development of DN. Therefore, it is necessary to identify new strategies that could specifically target on DN.
Recent studies have shown that chronic inflammation plays critical roles in promoting the development and progression of DN [5], [6], [7]. Macrophages are key inflammatory cells mediating kidney inflammation in DN and other types of renal disease. It has been found that macrophages accumulation is substantially increased in kidney tissue and associated with the progression of renal injury and a decline in renal function in experimental and human diabetes [8], [9], [10]. More important, several experimental studies have shown that different therapeutic strategies which can inhibit macrophage infiltration directly or indirectly can prevent the development or ameliorate renal injury in diabetes [11], [12], [13]. All these indicate that macrophage-mediated renal injury plays an important role in the development of DN.
An emerging body of studies have found that mesenchymal stem cells (MSCs) may play specific roles as immunomodulators in a wide array of disease [14], [15], [16], [17], [18], [19] due to their immunomodulatory properties including suppression of T cell proliferation [20], influencing dendritic cell (DC) maturation and function [21], [22], supression of B cell proliferation and terminal differentiation [23], etc. Recently, there is increasing evidence to suggest that the immunomodulatory effects of MSCs on macrophages is also a critical mechanism in the amelioration of inflammation-related disease, such as wounding healing, sepsis, acute myocardial infarction and renal ischemia reperfusion injury [24], [25], [26], [27]. However, the interactions between MSCs and macrophages in the process of DN are poorly understood.
Based on these findings, we hypothesized that MSCs may be effective on macrophage infiltration in kidney tissue of DN. In present study, we tested our strategy by transplanting bone marrow-derived MSCs to streptozotocin (STZ)-induced diabetic rats to explore the effect of MSCs on monocyte chemoattractant protein-1 (MCP-1) expression, macrophages infiltration and pro-inflammatory cytokines expression including IL-1β, IL-6 and TNFαin diabetic kidney.
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Animals
Female Wistar rats weighing 200–250 g were purchased from animal experimental center of Shandong University, China. They were given free access to food and water throughout the study. Animal studies were carried out in accordance with the guidelines of the Animal Ethics Committee of the Shandong University, which are consistent with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Diabetes model establishment
Diabetes was induced in the female Wistar rats by a single intraperitoneal
Characterization of rat MSCs
Bone marrow-derived MSCs from Wistar rats were adherent cultured with a typical fibroblast-like morphology (Fig. 1-A). They were able to differentiate into adipogenic and osteogenic cells (Fig. 1-B, C). Flow cytometric analysis showed that MSCs were positive for CD29 (99.56%), CD90 (96.26%), CD44 (88.76%), and negative for CD34 (3.80%), CD45 (1.99%), CD11b (19.03%).
MSCs tracking
MSCs transducted with GFP by lentiviral vector at the MOI of 20 resulted in a high transduction efficiency, more than 80% MSCs
Discussion
There was no doubt that MSCs played an active role in the treatment of DN, as revealed by amelioration of biochemical, physical parameters and glomerular fibrosis. In the current study, we intended to explore the mechanisms that mediate the therapeutic effects of MSCs on DN.
The diabetic animal model induced by a single intraperitoneal injection of 60 mg/kg STZ is well documented to produce hyperglycemia and insulinitis similar to human counterparts [32]. It has also been reported that 8 weeks
Conflict of interest statement
There is no conflict of interest to report.
Financial disclosure
This study was supported by the Innovation Foundation of Shandong University (No. 2009JC022).
Acknowledgements
We thank the laboratory animal center of the Second Hospital of Shandong University for the excellent rat care. We also thank Central Laboratory of the Second Hospital of Shandong University for providing the excellent experimental equipment.
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These authors contributed equally to this work and should be considered co-corresponding authors.