Role of the β-adrenergic Receptor in Podocyte Injury and Recovery

Overview

Journal Pharmacol Rep

Specialty Pharmacology

Date 2024 Apr 26

PMID 38668812

Authors

Ehtesham Arif

Ashish K Solanki

Bushra Rahman

Bethany Wolf

Rick G Schnellmann

Deepak Nihalani

Joshua H Lipschutz

Affiliations

Soon will be listed here.

Abstract

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 β-adrenergic receptor (β-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 β-AR or if it occurred through "off-target" effects.

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

References

Haraldsson B, Nystrom J, Deen W . Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008; 88(2):451-87. DOI: 10.1152/physrev.00055.2006. View

Brinkkoetter P, Ising C, Benzing T . The role of the podocyte in albumin filtration. Nat Rev Nephrol. 2013; 9(6):328-36. DOI: 10.1038/nrneph.2013.78. View

Torban E, Braun F, Wanner N, Takano T, Goodyer P, Lennon R . From podocyte biology to novel cures for glomerular disease. Kidney Int. 2019; 96(4):850-861. DOI: 10.1016/j.kint.2019.05.015. View

Durvasula R, Shankland S . Podocyte injury and targeting therapy: an update. Curr Opin Nephrol Hypertens. 2005; 15(1):1-7. DOI: 10.1097/01.mnh.0000199012.79670.0b. View

Bhargava P, Janda J, Schnellmann R . Elucidation of cGMP-dependent induction of mitochondrial biogenesis through PKG and p38 MAPK in the kidney. Am J Physiol Renal Physiol. 2019; 318(2):F322-F328. PMC: 7052650. DOI: 10.1152/ajprenal.00533.2019. View

Arif E, Nihalani D . Beta2-adrenergic receptor in kidney biology: A current prospective. Nephrology (Carlton). 2019; 24(5):497-503. DOI: 10.1111/nep.13584. View

Cameron R, Gibbs W, Miller S, Dupre T, Megyesi J, Beeson C . Proximal Tubule -Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury. J Pharmacol Exp Ther. 2019; 369(1):173-180. PMC: 11046739. DOI: 10.1124/jpet.118.252833. View

Johnstone D, Zhang J, George B, Leon C, Gachet C, Wong H . Podocyte-specific deletion of Myh9 encoding nonmuscle myosin heavy chain 2A predisposes mice to glomerulopathy. Mol Cell Biol. 2011; 31(10):2162-70. PMC: 3133349. DOI: 10.1128/MCB.05234-11. View

Hizawa N . Pharmacogenetics of β2-agonists. Allergol Int. 2011; 60(3):239-46. DOI: 10.2332/allergolint.11-RAI-0317. View

10.

Syamsu , Yusuf I, Budu , Patellongi I . The effect of polymorphism of the beta-2 adrenergic receptor on the response to beta-2 agonist in bronchial asthma patients. Acta Med Indones. 2007; 39(1):8-12. View

11.

Johnson M . Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol. 2006; 117(1):18-24. DOI: 10.1016/j.jaci.2005.11.012. View

12.

Wachter S, Gilbert E . Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology. 2012; 122(2):104-12. DOI: 10.1159/000339271. View

13.

Arif E, Solanki A, Srivastava P, Rahman B, Fitzgibbon W, Deng P . Mitochondrial biogenesis induced by the β2-adrenergic receptor agonist formoterol accelerates podocyte recovery from glomerular injury. Kidney Int. 2019; 96(3):656-673. PMC: 6708766. DOI: 10.1016/j.kint.2019.03.023. View

14.

Hinoi E, Gao N, Jung D, Yadav V, Yoshizawa T, Myers Jr M . The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol. 2008; 183(7):1235-42. PMC: 2606962. DOI: 10.1083/jcb.200809113. View

15.

Scholpa N, Simmons E, Tilley D, Schnellmann R . β-adrenergic receptor-mediated mitochondrial biogenesis improves skeletal muscle recovery following spinal cord injury. Exp Neurol. 2019; 322:113064. PMC: 7751764. DOI: 10.1016/j.expneurol.2019.113064. View

16.

Velez J, Arif E, Rodgers J, Hicks M, Arthur J, Nihalani D . Deficiency of the Angiotensinase Aminopeptidase A Increases Susceptibility to Glomerular Injury. J Am Soc Nephrol. 2017; 28(7):2119-2132. PMC: 5491295. DOI: 10.1681/ASN.2016111166. View

17.

Verma R, Kovari I, Soofi A, Nihalani D, Patrie K, Holzman L . Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006; 116(5):1346-59. PMC: 1401486. DOI: 10.1172/JCI27414. View

18.

Arif E, Rathore Y, Kumari B, Ashish F, Wong H, Holzman L . Slit diaphragm protein Neph1 and its signaling: a novel therapeutic target for protection of podocytes against glomerular injury. J Biol Chem. 2014; 289(14):9502-18. PMC: 3975002. DOI: 10.1074/jbc.M113.505743. View

19.

Sagar A, Arif E, Solanki A, Srivastava P, Janech M, Kim S . Targeting Neph1 and ZO-1 protein-protein interaction in podocytes prevents podocyte injury and preserves glomerular filtration function. Sci Rep. 2017; 7(1):12047. PMC: 5608913. DOI: 10.1038/s41598-017-12134-8. View

20.

Masszi A, Fan L, Rosivall L, McCulloch C, Rotstein O, Mucsi I . Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol. 2004; 165(6):1955-67. PMC: 1618715. DOI: 10.1016/s0002-9440(10)63247-6. View