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Abstract: FR-PO398

Amodiaquine and Chloroquine Attenuate Mitochondrial Abnormalities in Diabetic Tubulopathy Presumably by AMPK Phosphorylation

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Lee, So-young, CHA Bundang Medical Center, CHA Univ., Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Yang, Dong Ho, Bundang CHA medical center, CHA university, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Kang, Jun mo, Bundang CHA medical center, CHA university, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Sung, Min ji, Bundang CHA medical center, CHA university, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Choi, Yubum, Bundang CHA medical center, CHA university, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Ahn, Wooyeol, CHA University, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Jung, Su Woong, Kyung Hee University Hospital at Gangdong, Kyung Hee University, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Lee, Soonchul, CHA Bundang Medical Center, CHA university, Seongnam, Gyeonggi-do, Korea (the Republic of)
Background

The activity of 5' AMP-activated protein kinase (AMPK), the major energy-sensing enzyme, was recently observed to be reduced in the kidneys of both diabetic mice and humans. Several previous studies showed that AMPK activators attenuate diabetic nephropathy, resulting in decreased albuminuria in diabetic mice.
Chloroquine (CQ), an antimalaric drug, has also been considered an essential therapy in patients with systemic lupus erythematosus (SLE). It was reported that withdrawal of amodiaquine (AQ), a derivative of chloroquine is related to lupus flares after medication cessation. Although the mechanisms by which these agents act on SLE are unclear, a recent study reported that chloroquine increased AMPK phosphorylation in myotube cells.
We investigated the effects of CQ and AQ on AMPK phosphorylation in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether CQ- or AQ-mediated AMPK activity restoration attenuated diabetic tubulopathy by normalizing mitochondrial fragmentation.

Methods

Human renal proximal epithelial cells (HKC8) were incubated in high-glucose conditions. Diabetes was induced with streptozotocin in male C57/BL6J mice.

Results

Treatment with CQ or AQ abolished high-glucose-induced phospho-AMPK and phosph-PGC1α down-regulation in HKC8 cells. Improvements in functional mitochondrial mass and balanced fusion/fission protein expression were observed in HKC8 cells after treatment with CQ or AQ in high-glucose conditions. Moreover, decreased mitochondrial ROS production and reduced apoptotic and fibrotic protein expression were noted in HKC8 cells after treatment with CQ or AQ, even in high-glucose conditions. CQ and AQ treatment effectively mitigated albuminuria and renal histopathologic changes and increased AMPK activity in the kidneys of diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased, and 8-OHdG content was low in the renal tubular cells of the CQ and AQ treatment groups compared with those of the diabetic control group.

Conclusion

Our results suggest that CQ and AQ may be useful treatments for patients with diabetic kidney disease. This work was supported by a National Research Foundation grant of Korea (NRF-2016R1C1B1013814) funded by the Korea government.

Funding

  • Government Support - Non-U.S.