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Abstract: FR-OR56

Sparsentan Improves Glomerular Endothelial and Podocyte Functions and Augments Protective Tissue Repair in a Mouse Model of Focal Segmental Glomerulosclerosis (FSGS)

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gyarmati, Georgina, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Deepak, Sachin K., University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Shroff, Urvi Nikhil, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Izuhara, Audrey, University of Southern California Keck School of Medicine, Los Angeles, California, United States
  • Komers, Radko, Travere Therapeutics Inc, San Diego, California, United States
  • Bedard, Patricia W., Travere Therapeutics Inc, San Diego, California, United States
  • Peti-Peterdi, Janos, University of Southern California Keck School of Medicine, Los Angeles, California, United States
Background

Emerging evidence indicates strong nephroprotection by dual antagonism of the endothelin (ET) type A (ETAR) and angiotensin (AngII) type 1 (AT1R) receptors with sparsentan (SP). Previously, we reported antiproteinuric and protective hemodynamic effects of SP in both FSGS and normal mouse kidneys and differences between SP and AT1R inhibition alone. This study investigated the glomerular cell and molecular mechanisms of SP’s protective effects in experimental FSGS.

Methods

Multiphoton microscopy (MPM) of the kidney in vivo was combined with urinalysis and histology. Glomerular endothelial surface layer (glycocalyx) thickness (FITC-WGA labeling), podocyte mitochondrial metabolism (MitoTracker-Red intensity), and endothelial and renin lineage single-cell fate-tracking using Confetti mice were measured in 6 months-old FSGS mice (TRPC6 overexpression) received either no drug, losartan (Los; 10 mg/kg/day), or SP (120 mg/kg/day) in custom rodent chow for 6 weeks.

Results

The heterogeneous segmental increase in glomerular endothelial glycocalyx observed in FSGS mice was fully restored by SP compared to the intermediate effects of Los. Similarly, MPM found clear elevation of mitochondrial membrane potential indicating oxidative stress in podocytes in FSGS, which was attenuated by both Los and SP. Moreover, compared to Los, SP resulted in a more robust increase in the number of Confetti+ cells of both renin and endothelial lineages, clones, and individual cells/clone in both the glomeruli and tubules of FSGS mice indicating active tissue remodeling in response to SP.

Conclusion

MPM imaging directly visualized the pleiotropic protective effects of SP in the intact living kidney of FSGS mice including restoration of glomerular endothelial surface layer and podocyte metabolic functions and enhanced endogenous tissue repair, in addition to the previously identified hemodynamic improvements. Compared to Los, SP was more effective in the long-term preservation of kidney structure and function and in augmenting endogenous tissue repair in experimental FSGS, which further underscores the importance of ET component in the nephroprotective actions of SP.

Funding

  • Commercial Support