Nuclear Export Inhibitor Selinexor Improves Kidney Function in a Rat Model of FSGS

Journal of the American Society of Nephrology, vol. 36

Abstract

Background: FSGS is primarily driven by podocyte damage. Nuclear pore complexes (NPCs) control the passage between cytoplasm and nucleoplasm. They mediate a highly selective bidirectional transport of proteins, RNAs and RNA-protein complexes, which results in a specific nuclear and cytoplasmic environment, essential for proper cell function. While NPCs normally disassemble and renew during mitosis, post-mitotic cells like podocytes lack this surveillance mechanism, which means there can be accumulation of defective NPCs. This study explores the therapeutic potential of selinexor (KPT-330), an XPO1 inhibitor targeting NPC function. Methods: Compound screening was performed in vitro using HeLa cells with compartmentalization defects. The therapeutic effect of KPT-330 was subsequently tested in vivo in Munich Wistar Froemter (MWF) rats with spontaneous FSGS development. Ten-week-old male MWF rats received KPT-330 for 10 weeks and were monitored for anadditional 20 weeks. Results: KPT-330, an XPO-1 inhibitor, restored NPC function in HeLa cells. Untreated MWF rats developed FSGS, with about 35% glomeruli showing glomerulosclerosis at week 40, along with reduced kidney function. KPT-330 improved kidney function, lowering serum creatinine and cystatin C in MWF rats. A reduction in glomerular area was also observed. However, other histopathological markers, such as glomerulosclerosis, podocyte density, and parietal epithelial cell activation, did not change significantly. Conclusion: KPT-330 enhanced renal function in MWF rats with FSGS but was insufficient to halt the progression of histological damage. Funding: Government Support – Non-U.S.

Authors 1

1. Anna Leitz Aachen Division of Nephrology and Clinical Immunology

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   Division of Nephrology and Clinical Immunology, RWTH University Clinic, Aachen, Germany;