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

Hao-Hsiang Chang,Chiang-Ting Chien,Shih-Ping Hsu

doi:10.3390/antiox9010002

Abstract

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.

Highlights

Glomerulonephritis (GN) is a constellation of heterogenous renal diseases featured as a shared pathophysiology of immune mediated glomerular inflammation [1,2]
The present study aimed to investigate the anti-oxidative stress mechanisms involved in the use of locally intrarenal transplantation, for reduction of possible adverse effect, of normoxic Mesenchymal stem cells (MSCs) and hypoxic-preconditioned mesenchymal stem cells (HMSCs) in the anti-thy1.1 GN rat model
Our present data displayed that intrarenal arterial administration of either MSCs or HMSCs ameliorates the severity of glomerulosclerosis and levels of proteinuria in the anti-Thy-1.1 induced rat GN model

Summary

Introduction

Glomerulonephritis (GN) is a constellation of heterogenous renal diseases featured as a shared pathophysiology of immune mediated glomerular inflammation [1,2]. Mesenchymal stem cells (MSCs) have been shown to improve renal functions in animal GN models [8], and in some refractory human lupus nephritis studies [9,10,11]. In these studies, MSCs cross-talked with target organs by secreting growth factors, cytokines, and prostaglandins, which regulate anti-inflammation, anti-apoptosis, and anti-fibrosis effects and enhance cell proliferation, survival, and angiogenesis to repair injured tissue. The present study aimed to investigate the anti-oxidative stress mechanisms involved in the use of locally intrarenal transplantation, for reduction of possible adverse effect, of normoxic MSCs and hypoxic-preconditioned mesenchymal stem cells (HMSCs) in the anti-thy1.1 GN rat model

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Results

Discussion

Conclusion