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Abstract: SA-PO498

Serpinc1/Antithrombin III Protects Against Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wang, Feng, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
  • Kong, Yiwei, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Liu, Xuanchen, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Usa, Kristie, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Geurts, Aron M., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Liang, Mingyu, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

Antithrombin III (ATIII), encoded by the gene Serpinc1, is a serine protease inhibitor in the coagulation cascade and exhibits significant anti-inflammatory properties. Inflammation contributes to the development of diabetic nephropathy. The aim of this study was to investigate the effect of Serpinc1/ATIII on diabetic nephropathy.

Methods

ATIII activity was analyzed in patients with diabetic nephropathy. Kidney injury and inflammation were evaluated in streptozotocin (STZ)-treated Serpinc1 heterozygous knockout (Serpinc1+/-) rats and in db/db mice treated with adeno-associated virus (AAV, serotype 8) carrying Serpinc1 gene. The effects of ATIII on macrophages and podocytes treated with high glucose were also examined in vitro.

Results

Diabetic patients with lower ATIII activities had a significantly higher incidence of macroalbuminuria and microalbuminuria (n=328, P<0.05). Albuminuria was exacerbated in STZ-treated Serpinc1+/- rats compared with STZ-treated wild-type littermates 8 weeks after diabetes induction (albuminuria 76.1±7.1mg/24hr in Serpinc1+/- rats vs 26.6±4.7mg/24hr in wild-type controls, n=6, P<0.05). Serpinc1 heterozygous knockout significantly exacerbated renal infiltration of macrophages and increased renal NF-κB activity and IL-6 and MCP-1 mRNA abundance in rats with STZ-induced diabetes. Serpinc1 overexpression in db/db mice reduced albuminuria (273.4±21.7μg/24hr in db/db mice treated with AAV-Serpinc1 vs 430.9±26.8μg/24hr db/db mice treated with AAV-control, n=6, P<0.05) and attenuated renal infiltration of macrophages and decreased renal NF-κB activity and IL-6 and MCP-1 abundance. Treatment with high glucose (25mM) significantly increased NF-κB activation and IL-6 abundance in macrophages and podocytes in vitro. Treatment with ATIII protein attenuated these effects of high glucose.

Conclusion

In conclusion, Serpinc1/ATIII reduces inflammation and attenuates diabetic nephropathy.

Funding

  • Other NIH Support