Abstract: SA-PO1091

Urinary L-Type Fatty Acid-Binding Protein Is Useful for Evaluation of the Renoprotective Effect of Bardoxolone Methyl, a Nuclear Factor Erythroid 2-Related Factor 2 Activator

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Hisamichi, Mikako, Division of Nephrology and Hypertension, St Marianna University Hospital, Kawasaki, Japan
  • Sugaya, Takeshi, Division of Nephrology and Hypertension, St Marianna University Hospital, Kawasaki, Japan
  • Kimura, Kenjiro, Tokyo Takanawa Hospital, Tokyo, Japan
  • Shibagaki, Yugo, Division of Nephrology and Hypertension, St Marianna University Hospital, Kawasaki, Japan
  • Ikemori, Atsuko, Division of Nephrology and Hypertension, St Marianna University Hospital, Kawasaki, Japan
Background

Nuclear 1 factor related factor 2 (Nrf2) activator has an anti-oxidant effect and is expected to be a new strategy for chronic kidney disease. Urinary tubular marker, L-type fatty acid-binding protein (L-FABP), is known to accurately reflect tubular damage in a variety of renal stress, especially in oxidative stress. The aim of this study is to reveal the utility of urinary L-FABP as an indicator of the renoprotective effect of bardoxolne metyl (BM), a Nrf2 activator, in renal injury model due to oxidative stress.

Methods

We used an aldosterone (Ald)- and salt-induced renal injury model, in which oxidative stress is strongly associated with onset of tubulointerstitial damage. Tubulointerstitial damage with urinary L-FABP was evaluated using human L-FABP chromosomal transgenic (L-FABP+/-) male mice. Male L-FABP+/- mice were divided into three groups: The Ald group received systemic aldosterone infusions via an osmotic minipump and were given 1% NaCl water for 35 days. The Ald-Nrf2 group was given BM intraperitoneally in addition to an injection of aldosterone and salt. The dose of the Nrf2 activator was gradually increased every 7 days, reaching 10mg/kg/daily and continued for 14 days. The control group was only given a vehicle.

Results


The administration of BM significantly increased renal expression of the Nrf2 target antioxidant gene. Tubulointerstitial damage was significantly ameliorated in the Ald-BM group compared to the Ald group. The increase in reactive oxygen species in the kidneys of the Ald group was significantly prevented in the Ald-BM group. The upregulation of human L-FABP expression induced in the kidneys and the increase in urinary L-FABP in the Ald group were significantly suppressed by BM administration. The dynamics of L-FABP were significantly and strongly correlated with the prevention of the tubular damage (r=0.63), inflammatory infiltration(r=0.68) and fibrosis (r=0.72) by the administration of BM.

Conclusion

Urinary L-FABP is a useful marker reflecting the therapeutic efficacy of BM in Ald- and salt-induced renal injury.

Funding

  • NIDDK Support