Abstract: TH-PO996
Activation of Non-MC1R-Mediated Melanocortinergic Signaling Ameliorates Podocytopathy and Proteinuria in Experimental Focal Segmental Glomerulosclerosis (FSGS)
Session Information
- Pathology and Lab Medicine: Basic
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1501 Pathology and Lab Medicine: Basic
Authors
- Qiao, Yingjin, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Wang, Pei, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Ge, Yan, Brown university, Providence, Rhode Island, United States
- Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
- Liu, Zhangsuo, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States
Background
The clinical effectiveness of melanocortin therapy with adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptor(MCR) conveys this beneficial effect is controversial. Moreover, it remains uncertain if a systemic or podocyte specific mechanism is involved. By harnessing the naturally occurring MC1R-null mice and using NDP-MSH, a potent nonsteroidogenic pan-MCR agonist, this study aims to validate if a podocyte-specific MC1R-mediated melanocortinergic signaling mediates the beneficial effect in glomerulopathy, as proposed recently.
Methods
FSGS was induced in wild-type (WT) and MC1R-null mice by Adriamycin, treated with NDP-MSH and was evaluated. Primary podocytes were injured with Adriamycin and cytopathy assessed.
Results
WT mice developed heavy proteinuria after Adriamycin insult, associated with progressive glomerulosclerosis and podocytopathy, marked by loss of podocin and synaptopodin, podocytopenia and extensive foot process effacement on electron microscopy. All these injurious effects were prominently attenuated by NDP-MSH. Surprisingly, MC1R deficiency in MC1R-null mice barely affected the severity of Adriamycin-elicited injury. Moreover, the beneficial effect of NDP-MSH was equally observed in MC1R-null mice to an magnitude comparable to that in WT mice, suggesting that MC1R is likely nonessential for the protective action. A direct podocyte effect seems to contribute, at least in part, to the beneficial effect of NDP-MSH, because Adriamycin-inflicted cytopathic signs in primary podocytes prepared from WT mice were all diminished by NDP-MSH, including loss of podocyte markers, apoptosis, de novo expression of podocytopathic B7-1, actin cytoskeleton disruption and podocyte hypermotility. Consistent with in vivo findings, NDP-MSH protected the MC1R-null podocytes against Adriamycin injury to a degree equal to that observed in WT podocytes, again suggesting that non-MC1R-transmitted melanocortinergic signaling is responsible for this direct podocyte protection.
Conclusion
Melanocortin therapy protects against podocyte injury and ameliorates proteinuria and glomerulopathy via a non-MC1R-mediated melanocortinergic signaling.
Funding
- NIDDK Support