Abstract: SA-PO123

Omentin1 Ameliorates Hyperglycemia or Hypoxia-Induced Podocyte Dysfunction by Activating AMP-Activating Protein Kinase

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Kobayashi, Hidetoshi, University of Yamanashi, Chuo, Japan
  • Furuya, Fumihiko, University of Yamanashi, Chuo, Japan
  • Ishii, Toshihisa, University of Yamanashi, Chuo, Japan
  • Kitamura, Kenichiro, University of Yamanashi, Chuo, Japan
Background

Increased albuminuria is associated with the loss of capillary wall permselectivity in podocytes and is one of the risk factors for end stage kidney disease (ESKD). Omentin1 is an adipocytokine and has anti-inflammatory and anti-atherogenic properties. The aim of this study is to elucidate whether serum omentin1 levels are associated with the progression of diabetic kidney disease (DKD) and to explore the molecular mechanisms by which omentin1 induces anti-diabetic properties.

Methods

One hundred twenty-five diabetes patients were followed up for 7 years. Logistic regression models were used to evaluate the association with progression of DKD. To explore the protective function of omentin1, we focused on the AMPK pathway in podocytes. We exposed cultured podocytes to hyperglycemia or hypoxia and analyzed the kinase activities and the expression of downstream pathway in the presence or absence of omentin1.

Results

During the observation, progression either to the next albuminuria level in 16 patients or to ESKD occurred in 5 patients. In these progressors of DKD, baseline of serum omentin1 was significantly low compared with non-progressors. Multiple regression analysis revealed that a significant inverse association between serum omentin1 levels and the progression of DKD. In cultured podocytes, omentin1 administration was associated with increased activity of AMPK, and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction under hyperglycemia or hypoxia, as evidenced by zona occludens1 translocation to the membrane. These omentin1-induced activation of AMPK pathways are mediated through the adiponectin receptor1 (AdipoR1) in podocyte since it was diminished by siRNA-mediated knockdown of AdipoR1. These effects seemed to be caused by reduction of oxidative stress, as AdipoR1 and AMPK activation both reduced protein levels of NADPH oxidative Nox4 in podocytes.

Conclusion

Decreased serum omentin1 levels predict the progression of DKD in diabetes patients. Our in vitro findings demonstrated that omentin1-bound AdipoR1 is one of the key regulator of albuminuria and progression of DKD, likely acting through the AMPK pathway to modulate oxidative stress in podocytes.