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Abstract: FR-PO911

β2-Adrenergic (β2-AR) Agonist Protects Mice from Glomerular Injury Through the Activation of β2-AR Receptor in Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Arif, Ehtesham, Medical University of South Carolina, Charleston, South Carolina, United States
  • Solanki, Ashish K., Medical University of South Carolina, Charleston, South Carolina, United States
  • Srivastava, Pankaj, Medical University of South Carolina, Charleston, South Carolina, United States
  • Rahman, Bushra, Medical University of South Carolina, Charleston, South Carolina, United States
  • Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States
  • Nihalani, Deepak, Medical University of South Carolina, Charleston, South Carolina, United States
Background

Podocytes have a remarkable ability to recover from injury, however, little is known about the recovery mechanisms involved in this process. In this report, we demonstrate that pharmacological activation of β2-AR dependent MB (mitochondrial biogenesis) is involved in the recovery of podocytes from injury in a PGC-1α dependent manner. We further demonstrate that the drug-induced podocyte recovery was significantly attenuated in podocyte-specific β2-AR knockout mice.

Methods

The β2-AR knockdown human podocytes were generated using specific shRNA, and the podocyte specific β2-AR knockout mice were generated by crossing β2-AR flox mice with podocin cre (B6.Cg-Tg(NPHS2-cre)295Lbh/J) mice to remove β2-AR protein specifically in podocytes. The effect of a potent, specific, and long-acting β2-AR agonist formoterol on MB was analyzed in control and β2-AR knockdown podocytes by evaluating mtDNA (mitochondrial-DNA) copy number. Formoterol-induced (1mg/kg body weight/day) recovery of renal function was analyzed in wild-type and β2-AR knockout mice by analyzing UACR, histological, ultrastructural and immunostaining analyses.

Results

β2-AR knockdown in cultured human podocytes reduced mtDNA copy number indicating β2-AR role in MB. While the podocyte-specific β2-AR knockout mice developed normally, interestingly, when these mice were injured by treatment with adriamycin or nephrotoxic serum, unlike their WT (wild type) littermates, they failed to recover in response to treatment with formoterol and showed diseased glomerular morphology with consistent albuminuria.

Conclusion

Overall, these results confirmed that β2-AR plays a critical role in podocytes recovery from injury and genetic deletion of β2-AR affects the ability of mice to recover from injury. Overall these results suggest β2-AR as a novel therapeutic target for treating podocytopathies.

Funding

  • NIDDK Support