AUTHOR=Ren Huiwen , Shao Ying , Wu Can , Lv Chuan , Zhou Yang , Wang Qiuyue 

TITLE=VASH-1 Regulates Oxidative Stress and Fibrosis in Diabetic Kidney Disease via SIRT1/HIF1α and TGFβ1/Smad3 Signaling Pathways

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2020.00137

DOI=10.3389/fmolb.2020.00137

ISSN=2296-889X

ABSTRACT=<p><bold>Aims:</bold> To investigate the role of Vasohibin-1 (VASH-1), silence information adjustment factor 2-related enzyme 1 (SIRT1)/hypoxic-inducible factor 1α (HIF1α) and transforming growth factor-β1 (TGFβ1) /Smad3 signaling pathways in oxidative stress and fibrosis of diabetic kidney disease (DKD).</p><p><bold>Materials and Methods:</bold> A diabetic rat model was established <italic>in vivo</italic> and rat mesangial cells (RMCs) were cultured <italic>in vitro</italic> with high glucose via transfection with <italic>Vash1</italic> small interfering RNA (siRNA), <italic>Hif1a</italic> siRNA, <italic>Sirt1</italic> siRNA and TGFβ1/Smad3 pathway inhibitor (SB431542). Renal histology was used to detect renal changes. Real-time PCR and western blot were used to analyze the expression of VASH-1, SIRT1, HIF1α, TGFβ1, Smad3, vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) and fibronectin (FN). Expression levels of tumor necrosis factor-α (TNFα), TGFβ1, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in rat tissues and cell culture supernatant were detected by ELISA and chemiluminescence assay, while cell proliferation was detected by CCK-8.</p><p><bold>Results:</bold> The level of VASH-1 in renal tissues of diabetic rats was decreased, while both high glucose and <italic>Vash1</italic> siRNA inhibited the expression of VASH-1 and SIRT1, increased the levels of HIF1α, TGFβ1, and Smad3 in RMCs, thus up-regulating oxidative stress and fibrosis factors, and abnormally increasing cell proliferation activity (<italic>P</italic> &lt; 0.05). However, inhibition of SIRT1/HIF1α signaling pathway only reduced TGFβ1 and Smad3 (<italic>P</italic> &lt; 0.05), while VASH-1 remained unchanged (<italic>P</italic> &gt; 0.05).</p><p><bold>Conclusion:</bold> VASH-1 was under-expressed in renal tissues of diabetic rats and regulated the pathological process of oxidative stress and fibrosis in DKD via downstream SIRT1/HIF1α and TGFβ1/Smad3 signaling pathways.</p>