Abstract
Aims: 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).Materials and Methods: A diabetic rat model was established in vivo and rat mesangial cells (RMCs) were cultured in vitro with high glucose via transfection with Vash1 small interfering RNA (siRNA), Hif1a siRNA, Sirt1 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.Results: The level of VASH-1 in renal tissues of diabetic rats was decreased, while both high glucose and Vash1 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 (P < 0.05). However, inhibition of SIRT1/HIF1α signaling pathway only reduced TGFβ1 and Smad3 (P < 0.05), while VASH-1 remained unchanged (P > 0.05).Conclusion: 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.
Highlights
Diabetic kidney disease (DKD) is the most common cause of endstage renal disease (ESRD), clinical manifestations of which are characterized by slow development of continuous proteinuria, eventually leading to renal failure, and pathological features such as glomerular basement membrane thickening, glomerular hypertrophy, abnormal proliferation of glomerular mesangial cells and deposits of extracellular matrix (ECM), and even glomerular and interstitial fibrosis
The level of VASH-1 in renal tissues of diabetic rats was decreased, while both high glucose and Vash1 small interfering RNA (siRNA) inhibited the expression of VASH-1 and silence information adjustment factor 2-related enzyme 1 (SIRT1), increased the levels of Hypoxia-inducible factor 1α (HIF1α), transforming growth factor β1 (TGFβ1), and Smad3 in rat mesangial cells (RMCs), up-regulating oxidative stress and fibrosis factors, and abnormally increasing cell proliferation activity (P < 0.05)
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
Summary
Diabetic kidney disease (DKD) is the most common cause of endstage renal disease (ESRD), clinical manifestations of which are characterized by slow development of continuous proteinuria, eventually leading to renal failure, and pathological features such as glomerular basement membrane thickening, glomerular hypertrophy, abnormal proliferation of glomerular mesangial cells and deposits of extracellular matrix (ECM), and even glomerular and interstitial fibrosis. Recent reports show that VASH-1 is present in glomeruli mesangial cells as well (Bergers and Hanahan, 2008), and VASH1 plays a potential protective role in kidney diseases via negative feedback (Brownlee et al, 2016). One recent study has indicated that silence information adjustment factor 2-related enzyme 1 (Sirtuin 1, SIRT1) and superoxide dismutase 2 (SOD2) are two important downstream targets for VASH-1 (Chen et al, 2015). VASH-1 was shown to play a possible antifibrosis role through the transforming growth factor β1 (TGFβ1) /Smad pathway (Didion and Faraci, 2005; Dei Cas and Gnudi, 2012). The specific mechanism of VASH-1 regulation for these downstream targets has not been clarified
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