Amelioration of Endoplasmic Reticulum Stress by Mesenchymal Stem Cells via Hepatocyte Growth Factor/c-Met Signaling in Obesity-Associated Kidney Injury

Stem Cells Transl Med. 2019 Sep;8(9):898-910. doi: 10.1002/sctm.18-0265. Epub 2019 May 3.

Abstract

Recent advances in the understanding of lipid metabolism suggest a critical role of endoplasmic reticulum (ER) stress in obesity-induced kidney injury. Hepatocyte growth factor (HGF) is a pleiotropic cytokine frequently featured in stem cell therapy with distinct renotropic benefits. This study aims to define the potential link between human induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs)/bone marrow-derived MSCs (BM-MSCs) and ER stress in lipotoxic kidney injury induced by palmitic acid (PA) in renal tubular cells and by high-fat diet (HFD) in mice. iPS-MSCs or BM-MSCs alleviated ER stress (by preventing induction of Bip, chop, and unfolded protein response), inflammation (Il6, Cxcl1, and Cxcl2), and apoptosis (Bax/Bcl2 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) in renal cortex of animals exposed to HFD thus mitigating histologic damage and albuminuria, via activating HGF/c-Met paracrine signaling that resulted in enhanced HGF secretion in the glomerular compartment and c-Met expression in the tubules. Coculture experiments identified glomerular endothelial cells (GECs) to be the exclusive source of glomerular HGF when incubated with either iPS-MSCs or BM-MSCs in the presence of PA. Furthermore, both GEC-derived HGF and exogenous recombinant HGF attenuated PA-induced ER stress in cultured tubular cells, and this effect was abrogated by a neutralizing anti-HGF antibody. Taken together, this study is the first to demonstrate that MSCs ameliorate lipotoxic kidney injury via a novel microenvironment-dependent paracrine HGF/c-Met signaling mechanism to suppress ER stress and its downstream pro-inflammatory and pro-apoptotic consequences. Stem Cells Translational Medicine 2019;8:898&910.

Keywords: Endoplasmic reticulum stress; Hepatocyte growth factor; Induced pluripotent stem cells; Lipotoxicity; Mesenchymal stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Coculture Techniques
  • Culture Media, Conditioned / chemistry
  • Culture Media, Conditioned / pharmacology
  • Diet, High-Fat
  • Endoplasmic Reticulum Stress* / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism*
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Tubules / cytology
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism
  • Obesity / pathology*
  • Palmitic Acid / toxicity
  • Paracrine Communication / drug effects
  • Proto-Oncogene Proteins c-met / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects

Substances

  • Culture Media, Conditioned
  • Recombinant Proteins
  • Palmitic Acid
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met