Abstract: SA-PO124

Inappropriate Expression of Angiopoietin-Like 2 Promotes Podocytes Dysfunction by Activating Focal Adhesion Kinase in Diabetic Kidney Disease

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

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

Angiopoietin-like protein 2 (Angptl2) is an adiopokine which was secreted by adipose tissue or macrophages and that its circulating level was closely related to systemic insulin resistance, and inflammation in both mice and humans. We assessed the relationship between Angptl2 and the prevalence of the progression of diabetic kidney disease (DKD) and clarified the molecular mechanism of Angptl2-associated dysfunctions of podocytes.

Methods

One hundred forty eight diabetes patients were followed up for 7 years. Logistic regression models for the progression at every stage of DKD were used to evaluate the predictive value of Angptl2. The potential benefit of using Angptl2 alone or together with albumin excretion rate (AER) and eGFR was assessed by receiver operating characteristic (ROC) curve analysis. Furthermore, we investigated the expression of Angptl2 in macrophages and the effects of recombinant Angptl2 on podocyte in vitro.

Results

Progression of DKD was defined as the passage from one stage to the next based on AER or eGFR. The odds ratio for the prevalence of the presence diabetes, fatty changes of liver, and chronic kidney disease increased with higher serum Angptl2 levels. Cohort study indicated that baseline of Anptl2 was an independent predictor of progression at all stages of DKD. Reduced leukocyte DNA methylation in the promoter region of Angptl2 is associated with the pro-inflammatory environment that characterized with diabetic patients with ESKD from controls. In murine podocytes, Angptl2 induced the activation of focal adhesion kinase (FAK) via integrin α5β1-integrin-linked kinase and translocation of zona occludens-1 in the membrane and alubumin permeability.

Conclusion

Increased serum Angptl2 levels predict the progression of DKD in diabetes patients. Our in vitro findings suggest that Angptl2 is a key regulator of albuminuria, likely acting through the FAK pathway.