足细胞
肾小球硬化
缺氧(环境)
内分泌学
医学
内科学
糖尿病肾病
伊诺斯
肾病
细胞标志蛋白
肾
肾小球
蛋白尿
肾小球肾炎
一氧化氮
一氧化氮合酶
糖尿病
蛋白尿
化学
氧气
有机化学
作者
Naoki Takahashi,Haruyoshi Yoshida,Hideki Kimura,Kazuko Kamiyama,Tomomi Kurose,H Sugimoto,Toshio Imura,Seiji Yokoi,Daisuke Mikami,Kenji Kasuno,Hiroyuki Kurosawa,Yoshiaki Hirayama,Hironobu Naiki,Masanori Hara,Masayuki Iwano
摘要
Abstract Background Chronic hypoxia may play a pivotal role in the development of diabetic nephropathy (DN). However, the precise mechanisms underlying progressive hypoxia-induced glomerular injury remain unclear. Methods We housed db/db mice in a hypoxia chamber (12% O2) for up to 16 weeks beginning at 8 weeks of age. Various urine, serum and kidney abnormalities and glomerular messenger RNA (mRNA) expression were compared with those in age-matched db/db mice housed under normoxia. Results Levels of urinary albumin and podocalyxin (PCX) were significantly higher in hypoxic mice early during hypoxia. Ultracentrifugation of urine samples revealed that podocytes in the hypoxic mice shed PCX-positive microparticles into the urine. After 16 weeks of hypoxia, the mice also had higher hematocrits with lower serum glucose and various degrees of mesangiolytic glomerulosclerosis with microaneurysms and the infrequent occurrence of nodular lesions. Immunohistologically, hypoxic mice showed significantly decreased endothelial cell densities early during hypoxia and decreased podocyte densities later. In both hypoxic and normoxic mice, glomerular macrophage and transforming growth factor-β1 (TGF-β1) staining significantly increased with aging, without changes in vascular endothelial growth factor or endothelial nitric oxide synthase (eNOS). Glomerular mRNA expression of monocyte chemoattractant protein-1, eNOS and TGF-β1 was significantly enhanced in the hypoxic mice. Conclusions These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.
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