Abstract: SA-PO139

Atrasentan Treatment Combined with RAAS Inhibition Increases Parietal Epithelial Cell Activation and Restores Podocyte Number

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Hudkins, Kelly L., University of Washington, Seattle, Washington, United States
  • Wietecha, Tomasz A., University of Washington, Seattle, Washington, United States
  • Steegh, Floortje, Academic Hospital Maastricht, Maastricht, Netherlands
  • Alpers, Charles E., University of Washington Medical Center, Seattle, Washington, United States
Background

BTBR ob/ob (OB) mice develop robust type 2 diabetes and nephropathy that resembles human DN, with mesangial expansion, podocyte loss and proteinuria. This study tested the treatment effect of atrasentan (A), an endothelin-1 receptor antagonist, with or without concurrent RAAS inhibition by losartan (L) in mice with established DN.

Methods

Groups of 18 week old OB and WT littermates were treated via drinking water with A (5 mg/kg/day), A plus L (25 mg/kg/day) or normal drinking water for 6 weeks. Mice were analyzed for renal function and morphologic manifestations of DN, including proteinuria, podocyte number, mesangial matrix expansion, glomerular inflammatory infiltration, ultrastructural morphology and parietal epithelial cell (PEC) activation.

Results

Mice treated with A or A plus L had a 3 fold decrease in average albumin creatinine ratio (ACR) after 6 weeks of treatment. Analysis of paired urine samples at 18w and 24w showed significant ACR reduction in 5 of 6 OB mice (p=0.017) treated with A. Serum creatinine levels also decreased in OB mice treated with A and A plus L (p< 0.05). Renal function improvement was accompanied by decreased glomerular mesangial matrix, increased macrophage infiltration, restoration of podocyte foot processes and an increase in podocyte number. Expression of CD44 and pERK 1/2, both markers of PEC activation, were significantly increased in OB vs. WT (p<0.05). Treatment with A alone increased CD44 and pERK 1/2 PEC expression, while A plus L treatment showed a further increase in CD44 expression but a decrease of pERK1/2. Glomerular expression of pS6, a surrogate of mTOR activation, is increased in OB vs. WT mice (p<0.05), and treatment with A and A plus L resulted in a significant decrease.

Conclusion

Atrasentan treatment resulted in improvement of renal function, matrix accumulation and podocyte number in BTBR ob/ob mice with established DN. Combined treatment with A plus L resulted in increased restoration of podocyte number compared to A alone. PEC activation was also increased in treated mice, while activation of the mTOR pathway was reduced by treatment. The benefit of combined A plus L treatment in patients with DN may occur through restoration of podocyte number, potentially via PEC cell activation and migration, and foot process integrity.

Funding

  • Commercial Support