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

• Main Authors: Bin Li, Joseph C. K. Leung, Loretta Y. Y. Chan, Wai Han Yiu, Ye Li, Sarah W. Y. Lok, Wing Han Liu, Kam Wa Chan, Hung Fat Tse, Kar Neng Lai, Sydney C. W. Tang
• Format: Article
• Language: English
• Published: Wiley 2019-09-01
• Series: Stem Cells Translational Medicine
• Subjects: Induced pluripotent stem cells; Mesenchymal stem cells; Hepatocyte growth factor; Endoplasmic reticulum stress; Lipotoxicity
• Online Access: https://doi.org/10.1002/sctm.18-0265
• ISSN: 2157-6564; 2157-6580

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