Abstract: PO1964
Olinciguat Protects Renal Function and Podocytes in In Vivo and In Vitro Models of Podocytopathies
Session Information
- Podocyte Biology
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Buys, Emmanuel S., Cyclerion, Cambridge, Massachusetts, United States
- Arif, Ehtesham, Medical University of South Carolina, Charleston, South Carolina, United States
- Marusic, Suzana, Hooke Laboratories, Lawrence, Massachusetts, United States
- Nihalani, Deepak, Medical University of South Carolina, Charleston, South Carolina, United States
Background
The nitric oxide (NO) receptor soluble guanylate cyclase (sGC) is a signal-transduction enzyme producing the secondary messenger cGMP. Impaired NO-sGC-cGMP signaling is associated with renal dysfunction. sGC stimulators, small molecules that enhance NO-mediated cGMP signaling, improve renal function in animal models of cardiorenal injury.
Methods
We studied the reno-protective effects of olinciguat, a clinical-stage sGC stimulator, by studying in vitro and in vivo models of glomerular injury.
Results
In an acute focal segmental glomerulosclerosis (FSGS) model of glomerular injury induced by nephrotoxic serum (NTS), treatment with olinciguat attenuated proteinuria and kidney pathology when compared to vehicle-treated mice. Additionally, olinciguat treatment prevented NTS-induced mislocalization of the slit diaphragm proteins synaptopodin and nephrin. Ultrastructural analysis by transmission electron microscopy revealed that podocyte foot process morphology was preserved in mice treated with olinciguat.
To further assess the protective effect of sGC stimulation on podocytes, human podocytes injured by exposure to protamine-sulfate (PS) were treated with olinciguat. Olinciguat treatment restored PS-induced damage of podocyte actin cytoskeleton organization and the localization of podocyte cell membrane proteins.
In the genetic MRL/MpJ-Faslpr/J mouse model of systemic lupus erythematosus (SLE), disease progression, assessed by increased proteinuria, was less pronounced in mice treated with the positive control cyclophosphamide or with olinciguat than in vehicle-treated mice. Fewer kidney lesions (interstitial infiltrates, tubular atrophy, tubular epithelium vacuolation, tubular and interstitial lesions, and glomerular lesions) were observed in mice treated with cyclophosphamide or olinciguat than in vehicle-treated mice. In contrast to cyclophosphamide, olinciguat treatment did not result in leukopenia, reduction in spleen weight, or lower anti-dsDNA antibody in serum, suggesting that olinciguat did not impact the auto-immune aspect of SLE.
Conclusion
In summary, olinciguat, an orally bioavailable sGC stimulator, exhibits significant reno-protective effects in nonclinical models and warrants further evaluation for the treatment of FSGS, other podocytopathies, or nephropathies associated with diseases such as sickle cell disease.
Funding
- Commercial Support –