Abstract: FR-PO343

Nrf2 Deletion Promotes the Progression from Acute Tubular Damage to Chronic Renal Fibrosis Induced by Unilateral Ureteral Obstruction

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Kong, Weiwei, The first hospital of China Medical University, Shenyang, China
  • Fu, Jingqi, School of Public Health, China Medical University, Shenyang, China
  • Jiao, Congcong, The first hospital of China Medical University, Shenyang, China
  • Guo, Guangying, The first hospital of China Medical University, Shenyang, China
  • Wang, Huihui, China Medical University, Shenyang, China
  • Wang, Lining, Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang, P. R. China, Shenyang, China
  • Pi, Jingbo, School of Public Health, China Medical University, Shenyang, China
  • Zhou, Hua, The first hospital of China Medical University, Shenyang, China
Background

The role of Nrf2 (nuclear factor erythroid 2–related factor 2) in the progression from acute kidney damage to chronic renal fibrosis in obstructive nephropathy remains unclear. We aimed to verify whether Nrf2 deletion aggregates the progress of renal injury induced by unilateral ureteral obstruction (UUO) and further to investigate its mechanism in Nrf2-knockout mice (Nrf2−/− mice).

Methods

Renal injury was induced by UUO in 54 male Nrf2+/+ mice and 36 male Nrf2−/− mice. The kidneys were collected at day 2, 5, and 14 after UUO and histological damage was evaluated by PAS or Masson staining. We compared tubular damage (cleaved caspase3 and PARP) on day 2, transdifferentiation (vimentin and PCNA) on day5, fibrosis (fibronectin and α-SMA), and inflammatory factors on day 14 after UUO in Nrf2−/− mice with Nrf2+/+ mice on protein and mRNA levels. The temporal renal Nrf2 expression was examined in the mice with immunohitochemistry staining and western blotting. In addition, Nrf2 was also evaluated in renal biopsies from the patients with acute, sub-acute, or chronic tubulointerstitial nephritis.

Results

Tubular damage significantly occurred on day 2; vimentin, fibronectin, and α-SMA increased on day 5 and 14 in Nrf2+/+ mice. Nrf2 downstream genes (Gclc and Ho-1) significantly increased from day 2 to 5, while Nrf2 protein remarkably rose on day 5 and 14 in Nrf2+/+ mice. Renal Nrf2 positive staining was upregulated in patients with acute, sub-acute, and chronic tubulointerstitial nephritis conmared with normal huamn kidneys. Nrf2 deficiency significantly enhanced tubular damage, apoptotic cells evaluated by TUNEL staining, and levels of cleaved caspase3 and PARP on day 2. Nrf2 deletion markedly increased the cells co-expressed with vimentin and PCNA on double immunofluorecent staining on day 5. Nrf2−/− mice showed overproduction of fibronectin, α-SMA, and profibrotic inflammatory response genes (Tgfβ1, Tnfα, and IL6) on day 14 after UUO.

Conclusion

Nrf2 deficiency aggregated acute tubular damage, transdifferentiation, inflammation, and fibrosis under sustained UUO condition. The renalprotective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by anti-apotosis and anti-inflammation. Nrf2 might be a potential therapeutic target for renal fibrosis.

Funding

  • Government Support - Non-U.S.