Role of the β₂-adrenergic receptor in podocyte injury and recovery

Background: Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β₂-adrenergic receptor (β₂-AR) agonist, induced mitochondrial biogenesis (MB) in podocytes and led to renoprotection in mice. However, it is not clear whether this effect was mediated by formoterol acting through the β₂-AR or if it occurred through "off-target" effects.

Methods: We genetically deleted the β₂-AR specifically in murine podocytes and used these mice to determine whether formoterol acting through the podocyte β₂-AR alone is sufficient for recovery of renal filtration function following injury. The podocyte-specific β₂-AR knockout mice (β₂-AR^fl/fl/PodCre) were generated by crossing β₂-AR floxed mice with podocin Cre (B6.Cg-Tg(NPHS2-cre)295Lbh/J) mice. These mice were then subjected to both acute and chronic glomerular injury using nephrotoxic serum (NTS) and adriamycin (ADR), respectively. The extent of injury was evaluated by measuring albuminuria and histological and immunostaining analysis of the murine kidney sections.

Results: A similar level of injury was observed in β₂-AR knockout and control mice; however, the β₂-AR^fl/fl/PodCre mice failed to recover in response to formoterol. Functional evaluation of the β₂-AR^fl/fl/PodCre mice following injury plus formoterol showed similar albuminuria and glomerular injury to control mice that were not treated with formoterol.

Conclusions: These results indicate that the podocyte β₂-AR is a critical component of the recovery mechanism and may serve as a novel therapeutic target for treating podocytopathies.