Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice
Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice
复制标题
慢性缺氧通过 db/db 小鼠系膜溶解和足细胞损伤加剧糖尿病肾小球硬化
DOI：
10.1093/ndt/gfaa074
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Masayuki Iwano.
中科院分区：
文献类型：
--
作者：
Naoki Takahashi;Haruyoshi Yoshida;Hideki Kimura;Kazuko Kamiyama;Tomomi Kurose;Hidehiro Sugimoto;Toshio Imura;Seiji Yokoi;Daisuke Mikami;Kenji Kasuno;Hiroyuki Kurosawa;Yoshiaki Hirayama;Hironobu Naiki;Masanori Hara;Masayuki Iwano.
BackgroundChronic 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.MethodsWe 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.ResultsLevels 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.ConclusionsThese results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.
