Abstract: TH-PO739

AdipoRon Ameliorates Diabetic Nephropathy through Activation of Intracellular Ca++-AMPK-PPARα in Type 2 Diabetes

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Kim, Yaeni, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Lim, Ji Hee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Min Young, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Eun Nim, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Yoon, Hye Eun, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Shin, Seok Joon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Choi, Bumsoon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

In diabetic nephropathy (DN), adiponectin’s renoprotective effects are related to the activation of AMP protein kinase (AMPK)-peroxisome proliferative-activated receptor (PPAR)α pathway by binding to adiponectin receptors, AdipoR1/R2, respectively

Methods

We investigated the expression of AdipoRs and their relevant intracellular pathway in twenty-seven type 2 diabetic patients and found the role of AdipoRon on DN in male C57BLKS/J db/db mice and glomerular endothelial cell (GEC) and podocyte.

Results

While the degree and extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal functional deterioration, the expression of AdipoR1/R2 and Ca++/calmodulin-dependent protein kinase kinase (CaMKK)b and number of phosphorylated liver-kinase B (LKB)-1and AMPK-positive cells in the glomerulus was significantly decreased even in earlier stages of human DN. Diabetes-induced alterations shown in human DN were relieved by AdipoRon in db/db mice. The protective role of AdipoRon occurred through a direct activation of intrarenal AdipoR1/R2, which in turn increased expression of CaMKKb-phospho-Ser431LKB1-phospho-Thr172AMPK-PPARα pathway independently of systemic effects of adiponectin. Subsequent their relevant intracellular pathways related to lipid accumulation and endothelial dysfunction were reduced by improving diabetes-induced oxidative stress and apoptosis in the kidney. In human GECs and murine podocytes exposed to high glucose, AdipoRon increased the expression of intracellular Ca++, which subsequently activated CaMKKb-phospho-Ser431LKB1-phospho-Thr172AMPK-PPARα and their downstream signals and resulted in decreased high glucose-induced oxidative stress, apoptosis, and endothelial dysfunction.

Conclusion

Our study suggests AdipoRon may be an effective therapeutic strategy for type 2 DN via ameliorating GEC and podocyte injury by the activation of intracellular Ca++-AMPK-PPARα pathway.

Funding

  • Private Foundation Support