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Open AccessArticle

Intrarenal Transplantation of Hypoxic Preconditioned Mesenchymal Stem Cells Improves Glomerulonephritis through Anti-Oxidation, Anti-ER Stress, Anti-Inflammation, Anti-Apoptosis, and Anti-Autophagy

by Hao-Hsiang Chang 1,2, Shih-Ping Hsu 1,3,*,† and Chiang-Ting Chien 1,*,†
1
School of Life Science, National Taiwan Normal University, Taipei 116, Taiwan
2
Department of Family Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan
3
Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contribute equally to this work.
Antioxidants 2020, 9(1), 2; https://doi.org/10.3390/antiox9010002
Received: 23 November 2019 / Revised: 9 December 2019 / Accepted: 16 December 2019 / Published: 18 December 2019
To confer further therapeutic potential and prevent some adverse effects by the mesenchymal stem cells (MSCs) transplantation, we explored the effects of locally intrarenal arterial administration of hypoxic preconditioned MSCs in the anti-Thy1.1 induced rat glomerulonephritis. Proteinuria, histochemical staining, and western blotting were used to explore the therapeutic effects and mechanisms. Locally intrarenal arterial MSCs transplantation successfully implanted the fluorescent or CD44 labeled MSCs in the nephritic glomeruli, ameliorated proteinuria, and glomerulosclerosis in nephritic rats. Hypoxic preconditioning significantly upregulated hypoxic inducible factor-1α/VEGF (HIF-1α/VEGF) in the MSCs and was more efficient than normoxic MSCs in reducing the degree of urinary protein, glomerulosclerosis, fibrosis, macrophage/monocyte infiltration, GRP78 mediated endoplasmic reticulum stress, Beclin-1/LC3-II mediated autophagy, and Bax/Bcl-2/caspase 3 mediated apoptosis. Hypoxic MSCs could further promote intranuclear nuclear factor (erythroid-derived 2, Nrf2) and reduce nuclear factor kappa B expression in nephritic kidneys. As compared to normoxic MSCs, hypoxic MSCs transplantation significantly upregulated the renal expression of anti-oxidative response elements/enzymes including glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione peroxidase, catalase, Mn, and Cu/Zn superoxide dismutase. In summary, intrarenal hypoxic preconditioning MSCs transplantation was more effective to activate hypoxic inducible factor-1α/VEGF/Nrf2 (HIF-1α/VEGF/Nrf2) signaling, preserve anti-oxidant proteins and anti-oxidative responsive element proteins, and subsequently reduce glomerular apoptosis, autophagy, and inflammation. View Full-Text
Keywords: apoptosis; autophagy; hypoxic preconditioning; mesenchymal stem cell; Nrf2; inflammation apoptosis; autophagy; hypoxic preconditioning; mesenchymal stem cell; Nrf2; inflammation
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MDPI and ACS Style

Chang, H.-H.; Hsu, S.-P.; Chien, C.-T. Intrarenal Transplantation of Hypoxic Preconditioned Mesenchymal Stem Cells Improves Glomerulonephritis through Anti-Oxidation, Anti-ER Stress, Anti-Inflammation, Anti-Apoptosis, and Anti-Autophagy. Antioxidants 2020, 9, 2.

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