Abstract: PO1710
Delayed Treatment with a Novel Highly Selective Small-Molecule Agonist of MC5R Attenuates Podocyte Injury and Proteinuria in Puromycin Aminonucleoside Nephrosis
Session Information
- Podocyte Pathobiology: Basic Science Studies and Animal Models
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Chen, Bohan, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
- Ge, Yan, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
- Dworkin, Lance D., University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
- Gong, Rujun, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, United States
Background
Clinical studies indicate that the melanocortin peptide ACTH is effective in inducing remission of nephrotic glomerulopathies like MCD and FSGS, even those resistant to steroids, suggesting that a steroid-independent melancortinergic mechanism might contribute. However, the type of melanocortin receptor (MCR) that conveys this beneficial effect as well as the underlying mechanisms remains controversial. Recently, burgeoning evidence suggests that MC5R is likely involved in glomerular pathobiology. This study aims to test the effectiveness of a novel highly selective MC5R agonist (MC5RA) in puromycin aminonucleoside (PAN) nephrosis.
Methods
MC5RA was generated by N-terminal modification of the melanocortin core tetrapeptide His-D-Phe-Arg-Trp-NH2 with an aromatic group, resulting in a triphenylpropionyl melanocortin analog with a 100-fold selective agonistic activity on MC5R. Rats were injured with a tail vein injection of PAN, and 5 days later, were randomized to daily MC5RA or vehicle treatment.
Results
Upon PAN injury, rats developed heavy proteinuria on day 5, entailing an established nephrotic glomerulopathy. Following vehicle treatment, proteinuria continued to progress on day 14 and was sustained till day 21, accompanied by evident histologic signs of podocytopathy, marked by ultrastructural lesions of glomeruli, including extensive effacement of podocyte foot processes and podocyte microvillus transformation, and concomitant with loss of podocyte homeostatic markers, such as synaptopodin and nephrin, and de novo expression of podocyte injury marker desmin. Rescue treatment with MC5RA significantly attenuated urine albumin excretion and mitigated the loss of podocyte marker proteins, resulting in improved podocyte ultrastructural changes. In vitro in cultured podocytes, MC5RA prevented the PAN-induced disruption of actin cytoskeleton integrity and apoptosis. Mechanistically, MC5RA treatment reinstated inhibitory phosphorylation and thus averted hyperactivity of GSK3β, a convergent point of multiple podocytopathic pathways, in PAN-injured podocytes in vitro and in vivo.
Conclusion
Pharmacologic targeting of MC5R by using the highly selective small-molecule agonist is likely a promising and feasible therapeutic strategy to improve proteinuria and podocyte injury in glomerular disease.
Funding
- NIDDK Support