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Abstract: TH-PO786

β2-Adrenergic Receptor Stimulation Accelerates Podocyte Recovery from Injury Through Increased Mitochondrial Biogenesis

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

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
  • Megyesi, Judit, University of Arkansas for Medical Science, Little Rock, Arkansas, United States
  • Janech, Michael G., Medical University of South Carolina, Charleston, South Carolina, United States
  • Kwon, Kenneth, Medical University of South Carolina, Charleston, South Carolina, United States
  • Collier, Justin B., 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

Mitochondrial biogenesis (MB) is an adaptive response required to meet the metabolic and energy demand during acute injury to various organs, including kidney suggesting that MB plays a central role in cellular recovery from injury. In this report, we demonstrate that β2-AR mediated MB accelerates the recovery of podocytes from injury.

Methods

RNA-Sequencing of inured podocytes was performed to identify differential gene expression of mitochondrial genes. Oxygen consumption rate in response to β2-AR activation was measured using sea-horse approach. Effect of β2-AR agonist formoterol on restoring injury-induced loss of actin cytoskeleton organization and localization of slit-diaphragm protein Neph1 was analyzed using confocal microscopy. Additionally, formoterol was used to stimulate β2-AR in mice and determine its ability to restore the loss of glomerular filtration function. The histological, ultrastructural and immunostaining analysis of kidney sections was performed to assess structural and molecular changes in treated mice kidneys. MtDNA copy number was estimated through the qPCR analysis.

Results

Injury induced significant upregulation of β2-AR along with PGC-1α and several key components of the mitochondrial ETC. The activation of β2-AR by formoterol showed remarkable restoration of injury-induced changes in actin cytoskeleton organization and loss of Neph1 at the podocyte cell membrane. Importantly, in a mouse model of NTS-induced glomerulonephritis, post NTS-injury when glomerular dysfunction was established, treatment with β2-AR agonist formoterol accelerated the recovery of glomerular function by reducing proteinuria and restoring kidney pathology. Immunoblotting and qPCR analysis showed that multiple proteins of the ETC were elevated and glomerular expression of the MB marker PGC-1α was restored. mtDNA copy number was significantly higher in mice treated with β2-AR agonist formoterol. Additionally, β2-AR knockdown in cultured podocytes significantly reduced mtDNA copy number and increased podocytes susceptibility to glomerular injury.

Conclusion

Overall, these results reveal β2-AR stimulation as a critical event required for podocyte recovery and identifies β2-AR agonist as a novel therapeutic target for treating podocytopathies.

Funding

  • NIDDK Support