Abstract
Mesenchymal stem cells (MSCs) have been shown to improve the outcome of acute renal injury models; but whether MSCs can delay renal failure in chronic kidney disease (CKD) remains unclear. In the present study, the were cultured in media containing various concentrations of basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate to investigate whether hepatocyte growth factor (HGF) secretion could be increased by the stimulation of these growth factors. Then, TGF-β1-treated renal interstitial fibroblast (NRK-49F), renal proximal tubular cells (NRK-52E) and podocytes were co-cultured with conditioned MSCs in the absence or presence of ascorbic acid 2-phosphate to quantify the protective effects of conditioned MSCs on renal cells. Moreover, male Sprague-Dawley rats were treated with 1 × 106 conditioned MSCs immediately after 5/6 nephrectomy and every other week through the tail vein for 14 weeks. It was found that basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate promoted HGF secretion in MSCs. Besides, conditioned MSCs were found to be protective against TGF-β1 induced epithelial-to-mesenchymal transition of NRK-52E and activation of NRK-49F cells. Furthermore, conditioned MSCs protected podocytes from TGF-β1-induced loss of synaptopodin, fibronectin induction, cell death and apoptosis. Rats transplanted with conditioned human MSCs had a significantly increase in creatinine clearance rate, decrease in glomerulosclerosis, interstitial fibrosis and increase in CD4+CD25+Foxp3+ regulatory T cells counts in splenocytes. Together, our studies indicated that conditioned MSCs preserve renal function by their anti-fibrotic and anti-inflammatory effects. Transplantation of conditioned MSCs may be useful in treating CKD.
Highlights
Tubulointerstitial fibrosis is the final common pathway to end stage renal disease regardless of disease aetiology [1]
To examine the effect of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and ascorbic acid 2-phosphate on Hepatocyte growth factor (HGF) secretion, the basal culture media was supplemented with bFGF (R&D Systems, Inc., Minneapolis, MN, USA) or EGF (R&D Systems, Inc.) at concentrations of 0, 1, 2, 4, 8, or 10 ng/ml in the absence or presence of ascorbic acid 2-phosphate
In addition Transforming growth factor-b1 (TGF-b1) induced increase in the expression of a-smooth muscle actin expression (SMA) protein in NRK-52E cells, which was inhibited by the addition of conditioned Mesenchymal stem cells (MSCs) in the absence or presence of ascorbic acid 2-phospate
Summary
Tubulointerstitial fibrosis is the final common pathway to end stage renal disease regardless of disease aetiology [1]. Growing evidence has implicated that EMT as one of the pathways leading to interstitial fibrosis in diseased kidneys [5,6,7,8]. Transforming growth factor-b1 (TGF-b1) is a strong EMT inducer in renal tubule cells in a dose-dependent manner by up-regulating de novo a-smooth muscle actin expression (SMA) and the down-regulation of the epithelial adhesion molecule E-cadherin [9, 10]. Hepatocyte growth factor (HGF) was first identified as a mitogen for mature hepatocyte. Hepatocyte growth factor administration and HGF gene therapy have potent therapeutic effects in cases of liver cirrhosis [13], lung fibrosis [14, 15] and chronic renal fibrosis [16]
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