Journal
PLOS ONE
Volume 9, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0090883
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Funding
- Research Grants Council of Hong Kong [HKU 778212]
- National Basic Research Program of China 973 program [2012CB517600, 2012CB517606]
- HKU Seed Funding for Basic Research
- Hong Kong Society of Nephrology Research
- Endowment Fund
- Hong Kong Concrete and the Continental Cement and Gypsum Co. Ltd.
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Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular injury that correlates with residual proteinuria, we hypothesized that BM-MSCs may exert modulatory effects on renal tubular inflammation and epithelial-to-mesenchymal transition (EMT) under a protein-overloaded milieu. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCs by albumin excess was a prerequisite for them to attenuate albumin-induced IL-6, IL-8, TNF-alpha, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-kappa B signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and alpha-SMA, FN and collagen IV overexpression, was also prevented by BM-MSC co-culture. Albumin-overloaded BM-MSCs per se retained their tri-lineage differentiation capacity and overexpressed hepatocyte growth factor (HGF) and TNF alpha-stimulating gene (TSG)-6 via P38 and NF-kappa B signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-alpha overexpression were suppressed by recombinant HGF treatment, while the upregulation of alpha-SMA, FN and collagen IV was attenuated by recombinant TSG-6. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. In vivo, albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN, tubular CCL-2 and CCL-5 expression, alpha-SMA and collagen IV accumulation independent of changes in proteinuria. These data suggest anti-inflammatory and anti-fibrotic roles of BM-MSCs on renal tubular cells under a protein overloaded condition, probably mediated via the paracrine action of HGF and TSG-6.
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