Mesenchymal stem cells modulate albumin-induced renal tubular inflammation and fibrosis

PLoS One. 2014 Mar 19;9(3):e90883. doi: 10.1371/journal.pone.0090883. eCollection 2014.

Abstract

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-α, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-κB signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and α-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 TNFα-stimulating gene (TSG)-6 via P38 and NF-κB signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-α overexpression were suppressed by recombinant HGF treatment, while the upregulation of α-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, α-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Albumins / pharmacology*
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism
  • Coculture Techniques
  • Collagen Type IV / genetics
  • Collagen Type IV / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibrosis / chemically induced
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fibrosis / prevention & control
  • Gene Expression Regulation
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Primary Cell Culture
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • ACTA2 protein, human
  • Actins
  • Albumins
  • CCL2 protein, human
  • CCL5 protein, human
  • Cell Adhesion Molecules
  • Chemokine CCL2
  • Chemokine CCL5
  • Collagen Type IV
  • HGF protein, human
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • TNFAIP6 protein, human
  • Tumor Necrosis Factor-alpha
  • Hepatocyte Growth Factor

Grants and funding

General Research Fund of the Research Grants Council (Grant number: HKU 778212) of Hong Kong, the National Basic Research Program of China 973 program no. 2012CB517600 (no. 2012CB517606), HKU Seed Funding for Basic Research, and the Hong Kong Society of Nephrology Research Grant 2010; W.H.Y. is partially supported by an Endowment Fund established for the “Yu Professorship in Nephrology” awarded to S.C.W.T. and the Hong Kong Concrete and the Continental Cement and Gypsum Co. Ltd. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Part of the results from this study was presented in abstract form at the American Society of Nephrology Renal Week, Nov 10-13, 2011, Philadelphia, PA, USA.