Role of the ₂-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 beta(2)-adrenergic receptor (beta(2)-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 beta(2)-AR or if it occurred through "off-target" effects. Methods We genetically deleted the beta(2)-AR specifically in murine podocytes and used these mice to determine whether formoterol acting through the podocyte beta(2)-AR alone is sufficient for recovery of renal filtration function following injury. The podocyte-specific beta(2)-AR knockout mice (beta(2)-AR(fl/fl)/PodCre) were generated by crossing beta(2)-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 beta(2)-AR knockout and control mice; however, the beta(2)-AR(fl/fl)/PodCre mice failed to recover in response to formoterol. Functional evaluation of the beta(2)-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 beta(2)-AR is a critical component of the recovery mechanism and may serve as a novel therapeutic target for treating podocytopathies.