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, non-dividing 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 Froemter (MWF) rats, a model for spontaneous FSGS development, aged 10 weeks, were treated with KPT-330 for 10 weeks and then observed for another 20 weeks. Improvements in kidney function were observed at the end of the 10-week 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 additional 20 weeks without treatment. Hyperlipidemia was significantly reduced immediately after the end of the 10-week KPT-330 treatment compared to 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 histological progression of glomerular damage.