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Abstract: PO0933

Severe Diabetic Glomerulosclerosis by Chronic Hypoxic Housing of db/db Mice: The Role of Mesangiolysis and Podocyte Injury

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Takahashi, Naoki, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
  • Yoshida, Haruyoshi, Sugita Genpaku Kinen Koritsu Obama Byoin, Obama, Fukui, Japan
  • Kimura, Hideki, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
  • Kamiyama, Kazuko, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
  • Yokoi, Seiji, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
  • Kasuno, Kenji, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
  • Kurosawa, Hiroyuki, Denka Seiken Kabushiki Kaisha Niigata Kojo, Gosen, Niigata, Japan
  • Hirayama, Yoshiaki, Denka Seiken Kabushiki Kaisha Niigata Kojo, Gosen, Niigata, Japan
  • Hara, Masanori, Iwamuro Health Promotion Center, Niigata, Niigata, Japan
  • Iwano, Masayuki, Fukui Daigaku Igakubu, Yoshida-gun, Fukui, Japan
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 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.

Conclusion

These results indicate that chronic hypoxia induces advanced glomerulosclerosis with accelerated albuminuria triggered by mesangiolysis and podocyte injury in a murine model of DN.

Summary of the glomerular changes in db/db mice exposed to chronic hypoxia.

Funding

  • Commercial Support