Kidney Week

Abstract: FR-PO911

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

Session Information

• Glomerular Diseases: Podocyte Biology - II
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Arif, Ehtesham, Medical University of South Carolina, Charleston, South Carolina, United States

Ehtesham Arif,

• Solanki, Ashish K., Medical University of South Carolina, Charleston, South Carolina, United States

Ashish K. Solanki,

• Srivastava, Pankaj, Medical University of South Carolina, Charleston, South Carolina, United States

Pankaj Srivastava,

• Rahman, Bushra, Medical University of South Carolina, Charleston, South Carolina, United States

Bushra Rahman,

• Schnellmann, Rick G., University of Arizona, Tucson, Arizona, United States

Rick G. Schnellmann,

• Nihalani, Deepak, Medical University of South Carolina, Charleston, South Carolina, United States

Deepak Nihalani,

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 β_2-AR as a novel therapeutic target for treating podocytopathies.

Funding

• NIDDK Support