Abstract: FR-PO912
Melanocortin 5 Receptor (MC5R) Signaling Protects Against Podocyte Injury and Proteinuria
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
- Chang, Mingyang, University of Toledo Medical Center, Toledo, Ohio, United States
- Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
- Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States
Background
Melanocortin therapeutics represented by ACTH has a demonstrable steroidogenic-independent antiproteinuric and glomerular protective effect. It remains unclear which melanocortin receptors (MCR) mediate this renoprotective activity. MC5R was the last MCR to be characterized and has been involved in both biophysiology and pathology. However, the role of MC5R in glomerular disease is unknown and was examined here.
Methods
Adriamycin(ADR) nephropathy was induced in MC5R knockout (KO) and wild-type (WT) mice. Proteinuria and glomerular injury were evaluated. In vitro, ADR-insulted murine podocytes were treated with a highly selective MC5R agonist and cellular injury assessed.
Results
Under physiological condition, KO were no different from WT mice and had normal kidney physiology and histology. Upon ADR injury, KO mice demonstrated an exacerbated glomerular injury, featured by heavier albuminuria and worsened glomerular pathology, including glomerulosclerosis, podocyte apoptosis, loss of podocyte markers and ultrastructural lesions in podocytes like foot process effacement and microvillous transformation. Mechanistically, GSK3β, a transducer downstream of MC5R signaling and key regulator of podocyte injury, was more active in glomeruli of KO mice after ADR injury. This was concomitant with a potentiated activation of NFκB RelA/p65, a cognate substrate of GSK3β, in glomeruli in KO mice, and reinforced de novo expression of NFκB-dependent podocytopathic mediators, including B7-1, cathepsin L and MCP-1, in podocytes. Moreover, paxillin, a focal adhesion-associated adaptor protein and GSK3β substrate, was more activated in glomeruli of KO mice after ADR injury, associated with more disruption of podocyte cytoskeleton, shown by filamentous actin staining. In consistency, in vitro in ADR-insulted podocytes, treatment with a MC5R agonist rectified GSK3β overactivity, suppressed NFκB activation and the consequent de novo expression of B7-1, cathepsin L and MCP-1, and inhibited paxillin phosphorylation, resulting in a protection against podocyte injury, marked by cell shrinkage, hypermotility, cytoskeleton disorganization and apoptosis. This protective activity was blunted by ectopic expression of a constitutively active GSK3β mutant, signifying the mediating role of GSK3β.
Conclusion
MC5R-mediated melanocortinergic signaling protects against podocyte injury and proteinuria.
Funding
- NIDDK Support