Endothelin ET A receptor blockade does not attenuate the rise in early markers of acute kidney injury following bilateral renal ischemia

The role of endothelin‐1 (ET‐1) in renal ischemia/reperfusion (I/R) injury is unclear. We tested whether pretreatment with a selective ET A receptor antagonist (ABT‐627; 10 mg/kg/d p.o., 3 days) would attenuate acute kidney injury in male C57BL/6 mice (n=5–8). At 24 h after 20 min bilateral renal ischemia, I/R significantly increased ET‐1 mRNA levels (qPCR) relative to sham‐operated mice in renal cortex (2 −ΔΔCT =6.7+/−2.3 vs 1.0+/−0.1; P=0.06), outer medulla (6.0+/−1.0 vs 1.0+/−0.1; P<0.01) and inner medulla (2.1+/−0.3 vs 1.1+/−0.3; P=0.05). Plasma creatinine concentration was also significantly increased in I/R (2.4+/−0.2mg/dL) compared to sham operated mice (1.0+/−0.1mg/dL); this was not attenuated by ABT‐627 (2.8+/−0.1 mg/dL). Neutrophil gelatinase‐associated lipocalin (NGAL) is produced by renal tubular cells in response to injury and was markedly increased in I/R versus sham‐operated kidneys in the renal cortex (2 −ΔΔCT =62+/−13 vs 1.1+/−0.2; P<0.05) and outer medulla (24+/−4 vs 1.3+/−0.4; P<0.05), and this effect was not significantly attenuated by treatment with ABT‐627 (70+/−25 and 34+/−9 for cortex and outer medulla). These data suggest that despite marked ET‐1 upregulation in the kidney following I/R, ET A receptor activation may not play a major role in the initial loss of renal function or in tubular injury within the first 24 h following I/R.