The nuclear export inhibitor selinexor improves kidney function in a rat model of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a common glomerular pathology characterized by podocyte injury, which can lead to kidney failure. Among the factors contributing to podocyte damage are mutations in nuclear pore complexes (NPCs), which regulate nuclear-cytoplasmic transport of proteins and RNAs. Defective NPCs can accumulate in highly differentiated, nondividing cells such as podocytes. However, their role in podocyte dysfunction is largely unexplored, particularly as a potential therapeutic target. To address this, we investigated the effects of selinexor (KPT-330), a drug that inhibits XPO1-mediated nuclear-cytoplasmic protein export. In HeLa cells, KPT-330 restored compromised NPC function. Munich Wistar Fröemter (MWF) rats, a model for spontaneous FSGS development, aged 10 wk, were treated with KPT-330 for 10 wk and then observed for another 20 wk. Improvements in kidney function were observed at the end of the 10-wk treatment period, with serum creatinine significantly lower in the KPT-330 group (34.11 ± 1.77 μmol/L) versus the vehicle group (39.25 ± 3.54 μmol/L, P < 0.01). Serum cystatin C levels remained lower in the KPT-330 group (3.62 ± 0.39 μg/mL) versus vehicle (4.19 ± 0.44 μg/mL, P < 0.05) after an additional 20 wk without treatment. Hyperlipidemia was significantly reduced immediately after the end of the 10-wk KPT-330 treatment compared with vehicle (triglyceride: 1.23 ± 0.34 mmol/L vs. 1.92 ± 0.4 mmol/L, P < 0.01; total cholesterol: 1.47 ± 0.08 mmol/L vs. 2.96 ± 0.44 mmol/L, P < 0.0001). However, histopathological parameters, including glomerulosclerosis, podocyte numbers, and activation of parietal epithelial cells, showed that kidney damage continued to progress. Thus, KPT-330 has beneficial effects on kidney function, but was not sufficient to halt the histological progression of glomerular damage.NEW & NOTEWORTHY Focal segmental glomerulosclerosis (FSGS) involves podocyte injury, potentially linked to dysfunctional nuclear pore complexes (NPCs). We show that selinexor (KPT-330), a nuclear export inhibitor, restores NPC function in vitro. In an FSGS rat model, selinexor improves kidney function, lowers serum creatinine and cystatin C levels, and reduces serum lipid levels. However, histological damage persists, indicating partial but not complete protection. These findings highlight NPC-targeted therapies as a potential strategy for treating FSGS.