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<p>Versican (VCAN) was found to facilitate diabetic nephropathy (DN) progression and be an effective diagnostic indicator of DN. However, the underlying mechanism of VCAN in the modulation of the apoptosis, inflammation and oxidative stress of DN is not revealed. In this study, we found that VCAN was up-regulated in kidney tissues from DN patients and high glucose (HG)-induced human renal glomerular endothelial cells (HRGECs). VCAN knockdown facilitated HG-induced HRGECs viability, reduced HRGECs apoptosis, decreased inflammatory cytokine levels (IL-1β, IL-6 and TNF-α), repressed reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) level. Besides, RNA N6-methyladenosine (m6A) expression was increased in HG-induced HRGECs. Methyltransferase-like 14 (METTL14) knockdown decreased VCAN protein level and repressed m6A modification level of VCAN. METTL14 knockdown also reduced VCAN mRNA stability in HRGECs cells by actinomycin D treatment, and suppressed the luciferase activity of VCAN WT in HRGECs. Moreover, METTL14 knockdown increased HG-induced HRGECs viability, decreased the apoptosis, down-regulated inflammatory cytokine levels and ROS level, but VCAN overexpression reversed these results. VCAN knockdown reduced sonic hedgehog (SHH), smoothened (SMO) and Gli1 protein levels, whereas Hedgehog pathway activator purmorphamine (PUR) reversed the inhibition of si-VCAN on these findings. VCAN knockdown reduced glomerular area and collagen deposition, alleviated mesangial matrix expansion, renal tubular injury and glomerular endothelial cells apoptosis in db/db mice. Therefore, VCAN was up-regulated in DN, and VCAN knockdown attenuated the apoptosis, inflammation and oxidative stress in HG-induced HRGECs and db/db mice via SHH signaling.</p>

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m6A Modified VCAN Promotes Glomerular Endothelial Cells Injury and Diabetic Nephropathy by SHH Pathway

  • 期刊论文

  • 发表日期：

    2026年2月18日

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  • Jie Jiang,
  • Jicheng Zhang,
  • Chao Wang,
  • Feng Wang

摘要

Versican (VCAN) was found to facilitate diabetic nephropathy (DN) progression and be an effective diagnostic indicator of DN. However, the underlying mechanism of VCAN in the modulation of the apoptosis, inflammation and oxidative stress of DN is not revealed. In this study, we found that VCAN was up-regulated in kidney tissues from DN patients and high glucose (HG)-induced human renal glomerular endothelial cells (HRGECs). VCAN knockdown facilitated HG-induced HRGECs viability, reduced HRGECs apoptosis, decreased inflammatory cytokine levels (IL-1β, IL-6 and TNF-α), repressed reactive oxygen species (ROS) and malondialdehyde (MDA) levels and increased superoxide dismutase (SOD) level. Besides, RNA N6-methyladenosine (m6A) expression was increased in HG-induced HRGECs. Methyltransferase-like 14 (METTL14) knockdown decreased VCAN protein level and repressed m6A modification level of VCAN. METTL14 knockdown also reduced VCAN mRNA stability in HRGECs cells by actinomycin D treatment, and suppressed the luciferase activity of VCAN WT in HRGECs. Moreover, METTL14 knockdown increased HG-induced HRGECs viability, decreased the apoptosis, down-regulated inflammatory cytokine levels and ROS level, but VCAN overexpression reversed these results. VCAN knockdown reduced sonic hedgehog (SHH), smoothened (SMO) and Gli1 protein levels, whereas Hedgehog pathway activator purmorphamine (PUR) reversed the inhibition of si-VCAN on these findings. VCAN knockdown reduced glomerular area and collagen deposition, alleviated mesangial matrix expansion, renal tubular injury and glomerular endothelial cells apoptosis in db/db mice. Therefore, VCAN was up-regulated in DN, and VCAN knockdown attenuated the apoptosis, inflammation and oxidative stress in HG-induced HRGECs and db/db mice via SHH signaling.