Effects of selective inhibition of reverse mode of Na(+)/Ca(2+) exchanger on rats with contrast-induced acute kidney injury

Abstract

Intracellular Ca(2+) overload is a key factor in contrast-induced renal tubular toxicity. Na(+)/Ca(2+) exchanger (NCX) system is one of main pathways of intracellular Ca(2+) overload. We explore the effects of KB-R7943, an inhibitor of reverse mode of NCX, on contrast-induced acute kidney injury (CI-AKI). Rats were divided into control, CI-AKI and pre-treatment groups with KB-R7943 (5, 10 mg/kg). CI-AKI was induced by diatrizoate administration in rats with cholesterol-supplemented diet for 8 weeks. Renal function and hemodynamics were determined at Day 1 post-administration. Renal histopathology was observed under light microscope. Renal tubular apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Renal endothelin-1 (ET-1) was measured by radioimmunoassay. The oxidative markers of renal malondialdehyde (MDA) and catalase (CAT) were measured. The expression of NCX was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Levels of serum creatinine (Scr, µmol/L ) in CI-AKI rats ((149 ± 35) µmol/L) were significantly higher than those of normal rats ((55 ± 4) µmol/L, P < 0.01). Renal ET-1, MDA and CAT, resistance index (RI) of renal blood vessels increased significantly in CI-AKI rats. The contrast-induced increases in Scr and RI of renal blood vessels were suppressed significantly and dose-dependently by pretreatment with KB-R7943. Histopathological and TUNEL results showed that contrast-induced severe renal tubular necrosis and apoptosis were significantly and dose-dependently attenuated by KB-R7943. KB-R7943 significantly suppressed the contrast-induced increments of ET-1, MDA and CAT. No significant changes in NCX1 mRNA expression were observed following contrast administration. Renal oxidative stress and ET-1 overproduction via the activation of reverse mode of NCX play an important role in the pathogenesis of CI-AKI. And inhibition of reverse mode of NCX expressed in renal tubular epithelial cell has protective effects on CI-AKI.