Abstract: FR-PO357

Febuxostat Attenuates ER Stress Mediated Kidney Injury in a Rat Model of Hyperuricemic Nephropathy

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Fan, Ying, Shanghai 6th People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
  • He, Li, Shanghai 6th People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
  • Xiao, Wenzhen, Mount Sinai School of Medicine, New York, New York, United States
  • Wen, Jiejun, Shanghai 6th People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
  • Dong, Yang, Shanghai 6th People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
  • He, John C., Mount Sinai School of Medicine, New York, New York, United States
  • Wang, Niansong, Shanghai 6th People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
Background

Hyperuricemia contributes to the renal tubular injury and kidney fibrosis. Febuxostat, a novel inhibitor of xanthine oxidase, has been widely used for the treatment of hyperuricemia and prevention of gout. Recent studies suggested that Urate-lowering therapy (ULT) by Febuxostat might also have cardiovascular and renal benefits, yet the the mechanism of this protective effect is unknown. Endoplasmic reticulum (ER) stress has been well recognized as one of the important mechanisms in the onset and progression of many kidney diseases. In recent studies, we identified a novel ER-associated gene, reticulon-1A (RTN1A), which is associated with the progression of kidney diseases. However, the exact role of RTN1A and ER stress in hyperuricemia induced kidney disease hasn’t been fully studied.

Methods

In the present study, we studied the expression of RTN1A and other ER Stress markers in kidney biopsies of patients with hyperuricemia-related kidney injury. We determined the role of RTN1A and ER stress in uric acid induced renal tubular cell injury in vitro as well as in a rat model of hyperuricemic nephropathy (HN). We also examined whether treatment of Febuxostat diminished ER stress and apoptosis of renal tubular cells and attenuated kidney injury in HN rat model.

Results

We found the expression of RTN1A and ER stress markers was significantly increased in kidney biopsies of patients with hyperuricemia-related kidney injury. In HN rat model established by oral administration of a mixture of adenine and potassium oxonate, increased expression of RTN1A and ER stress were shown in tubular and interstitial compartment of rat kidneys. Treatment of Febuxostat not only attenuated ER stress mediated renal tubular injury and tubulointerstitial fibrosis, but also reduced uric acid crystals deposition in HN rat kidneys. In vitro, Febuxostat also suppressed uric acid-induced ER stress and apoptosis in cultured tubular cells.

Conclusion

In conclusion, RTN1A and ER stress mediate tubular cell injury and kidney fibrosis in hyperuricemia induced nephropathy. ULT with Febuxostat attenuates uric-acid induced ER stress in renal tubular cells and the progression of HN. This study suggests a therapeutic role of Febuxostat in hyperuricemia-related CKD.

Funding

  • Government Support - Non-U.S.