Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice
| Autor: | Yoshiaki Hirayama, Toshio Imura, Kazuko Kamiyama, Haruyoshi Yoshida, Hironobu Naiki, Hidehiro Sugimoto, Masanori Hara, Daisuke Mikami, Seiji Yokoi, Naoki Takahashi, Hiroyuki Kurosawa, Tomomi Kurose, Hideki Kimura, Kenji Kasuno, Masayuki Iwano |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A 0301 basic medicine medicine.medical_specialty Nitric Oxide Synthase Type III 030232 urology & nephrology Mice Inbred Strains Diabetes Mellitus Experimental Podocyte Diabetes Complications Transforming Growth Factor beta1 Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Diabetic Nephropathies Hypoxia Transplantation Podocytes business.industry Glomerulosclerosis Hypoxia (medical) medicine.disease Glomerular Mesangium Vascular endothelial growth factor Vascular endothelial growth factor A 030104 developmental biology Endocrinology medicine.anatomical_structure Podocalyxin chemistry Mesangiolysis Nephrology Albuminuria medicine.symptom business |
| Zdroj: | Nephrology Dialysis Transplantation. 35:1678-1688 |
| ISSN: | 1460-2385 0931-0509 |
| DOI: | 10.1093/ndt/gfaa074 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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