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Abstract: SA-PO382

Proteasome Inhibitors (PIs) Reduce PAN Induced Proteinuria by Enhancing FOXO3a/β-Catenin Complex in Minimal Change Disease (MCD)

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Vashistha, Himanshu, Ochsner Health System, New Orleans, Louisiana, United States
  • Abbruscato, Frank C., Ochsner Health System, New Orleans, Louisiana, United States
  • Baliga, Radhakrishna, LSU Health Sciences Center, Shreveport, Louisiana, United States
Background

Proteasomes play a major role in the pathophysiology of several disease processes in part through its action on a crucial transcription factor, nuclear factor-kappa B (NF-κB). NF-κB regulates the expression of a variety of inflammatory genes and plays a major role in MCD. The role of PIs in ongoing glomerular injury and the potential beneficial effects of PIs have not been previously examined. We show here that administration of PIs resulted in marked protection against puromycin aminonucleoside (PAN) -induced proteinuria by enhancing nuclear FOXO3a/β-Catenin complex, increasing expression of antioxidant enzymes and attenuates reactive oxygen species (ROS).

Methods

MCD was induced in rats by injecting PAN IV as a single dose and proteinuria measured as albumin to creatinine ratio (ACR) (µg/mg) until day 10. MG-132 was administered by osmotic pumps and Carfilzomib (CAR) was administered IV. Proteins were analyzed by Western Blot and immunocytochemistry. Immunohistochemical analysis was also performed on the kidney cortical sections.

Results

Administration of MG-132 and CAR prevented PAN induced proteinuria (PAN 147±29, MG132+PAN 98±32*, CAR+PAN 75+18*; P<0.05* compared to PAN alone). This was accompanied by marked decrease in lipid peroxidation in PIs-treated rats compared to PAN alone. MG-132 significantly decreased the nuclear translocation of NF-KB, activation of IL-6, up regulation of CYP, significantly reduced H2O2 release and 8-Oxo-dG expression in cultured human podocytes. Electron Microscopy data showed that MG-132 and CAR treatment prevented foot process effacement of podocytes. Immunohistochemical analysis of cortical sections of PIs treated rats and immunocytochemical analysis of cultured human podocytes treated with PIs revealed increased β-Catenin and FOXO3a colocalization. Human podocytes treated with PIs showed upregulated PAN induced HO-1 and SOD with significant decrease in cell death.

Conclusion

These in vitro and in vivo data imply the crucial role of proteasome in progressive glomerular injury. CAR, which is currently used in humans should be considered as a potential therapeutic alternative in MCD.