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Stem Cells Transl Med. 2019 May 3. doi: 10.1002/sctm.18-0265. [Epub ahead of print]

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

Author information

1
Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.
2
Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.

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.

KEYWORDS:

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

PMID:
31054183
DOI:
10.1002/sctm.18-0265
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