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

OBJECTIVE: 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). METHODS: 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). RESULTS: 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. CONCLUSION: 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.

[Effects of hypercholesterolemia on contrast media-induced nephrotoxicity in rats].

OBJECTIVE: To explore the effects of short- and long-term dietary hypercholesterolemia on contrast media-induced nephrotoxicity in rats. METHODS: The male Wistar rats were fed either a normal rodent diet or a high cholesterol diet. At the end of 2 and 8 weeks, 8 rats from each group received a tail vein injection of either Iohexol injection (groups NC and HC) or vehicle (groups N and H). Blood lipid, renal function, renal hemodynamics, renal and urinary prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), renal nitric oxide and malondialdehyde (MDA) were determined at Day 1 following the administration of contrast media. RESULTS: The dosing of contrast media induced obviously increased serum creatinine compared with normal rats ((185 ± 28) vs (53 ± 3) µmol/L, P < 0.01) and severe renal tubular necrosis in rats with a high cholesterol diet for 8 weeks but did not in normal-diet rats or rats with a high cholesterol diet for 2 weeks. The renal and urinary levels of PGE2 and TXB2 increased significantly in rats of groups H and HC at the end of 8 weeks. The renal production of nitric oxide decreased while the concentration of MDA increased markedly in groups HC and H at the end of 8 weeks. CONCLUSION: Long-term hypercholesterolemia appears to be a risk factor of contrast media-induced acute renal failure. And it may be associated with the disorder of intrarenal prostaglandins and the abnormality of renal nitric oxide system as induced by lipid peroxidation.

Dietary hypercholesterolemia aggravates contrast media-induced nephropathy.

BACKGROUND: Contrast media administration can result in severe nephrotoxicity under pathological conditions such as diabetic nephropathy, congestive heart failure, dehydration, et al. The purpose of this study was to evaluate the effects of dietary hypercholesterolemia on contrast media-induced changes in renal function, blood flow, and histopathology. METHODS: Rats were fed either on a normal rodent diet (group N) or a high-cholesterol supplemented diet (group H; 4% cholesterol and 1% cholic acid) for 8 weeks. Half of the animals (n = 6) from each diet group were then given a tail vein injection of 60% diatrizoate (6 ml/kg; group NC and group HC) and the other half were administered saline. Total serum cholesterol, triglyceride, serum creatinine, creatinine clearance rate, fractional excretion of sodium and potassium, and cortical nitric oxide production were determined one day following contrast media administration. Renal blood flow was determined by color Doppler flow imaging and pulsed-mode Doppler. Renal histopathology was observed by light microscopy. RESULTS: Total serum cholesterol and resistance indices of renal blood vessels increased significantly, while creatinine clearance rate and production of nitric oxide in the renal cortex decreased markedly in group HC and group H when compared to group N and group NC. The creatinine clearance rate decreased significantly in group HC compared to group H. Serum creatinine levels and fractional excretion of sodium and potassium in group HC were significantly higher than those in the other three groups. Severe tubular degeneration and necrosis, protein cast accumulation, and medullary congestion were found in group HC. CONCLUSION: Hypercholesterolemia is a risk factor for contrast media-induced nephropathy. Hypercholesterolemia aggravates contrast media-induced nephrotoxicity through the reduced production of nitric oxide.