Atorvastatin alleviates iodinated contrast media-induced cytotoxicity in human proximal renal tubular epithelial cells.

Contrast media (CM)-induced nephropathy (CIN) is a serious complication of intravascularly applied radiocontrast media. At present, no drugs have been approved for the prevention of CIN. The present study aimed to explore the effects and potential mechanisms of atorvastatin on iodinated CM-induced cytotoxicity in the human proximal renal tubular epithelial cells. The cytotoxic effect of iohexol (50, 100 and 200 mg I/ml) and the protective effect of atorvastatin pretreatment (1, 20 and 40 µM) were assessed. The cytotoxicity of iohexol was evaluated via the MTT cell viability and lactate dehydrogenase assays. The amount of apoptotic cells was determined by flow cytometry. Morphological changes in HK-2 cells were observed via transmission electron microscopy. The mRNA expression of NOX4 and p22phox was measured through reverse transcription-quantitative polymerase chain reaction analysis. The cytotoxicity was induced by iohexol in HK-2 cells. Atorvastatin was identified to significantly alleviate the suppression of cell viability induced by iohexol. Notably, 40 µM atorvastatin also significantly reduced the mRNA expression of intracellular NOX4 and p22phox, and the percentage of apoptotic cells. Furthermore, morphological changes characteristic of injured cells were alleviated by atorvastatin pretreatment. These results suggest that atorvastatin exhibits a protective effect on HK-2 cells against iohexol-induced cytotoxicity through the downregulation of NOX4 and p22phox. Thus, atorvastatin is a potential therapeutic agent for the prevention of CIN and required further study.

Urinary KIM-1, IL-18 and Cys-c as early predictive biomarkers in gadolinium-based contrast-induced nephropathy in the elderly patients.

BACKGROUND/AIMS: This study was designed to investigate whether urinary kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18) and cystatin C (Cys-C) are early predictive biomarkers for gadolinium-based contrast-induced nephropathy (Gd-CIN) in the elderly patients undergoing gadolinium-enhanced magnetic resonance imaging (MRI). METHODS: 60 elderly patients undergoing enhanced MRI using gadolinium-based contrast media were enrolled. Urine samples were collected before and 24 hours and 48 hours after the procedure, and KIM-1, IL-18 and Cys-C levels were measured by using an ELLSA kit respectively. Serum samples before and 24 hours and 48 hours after the procedure were also collected, and creatinine was measured by automatic biochemical analyzer. RESULTS: Gd-CIN was diagnosed in 8 of 60 (13.3%) patients. At 24 hours after MRI with gadolinium administration in the Gd-CIN group, the urinary KIM-1, IL-18 and Cys-C were significantly increased. Logistic regression analysis showed that urinary KIM-1 and IL-18 at 24 hours after gadolinium injection were independent predictive markers of Gd-CIN. The predictable time of acute kidney injury (AKI) onset determined by urinary KIM-1, IL-18 and Cys-C was 24 hours earlier than by serum creatinine. CONCLUSIONS: Urinary KIM-1, IL-18 and Cys-C could be early predictive biomarkers of Gd-CIN in the elderly patients, which showed a good performance in early diagnosis of Gd-CIN as compared with serum creatinine.

Aged rats are susceptible to nephrotoxicity induced by iodinated contrast media.

OBJECTIVE: The objective of this study is to evaluate the effect and mechanism of aging on iodinated-contrast-media-induced nephropathy in male rats. METHODS: Twenty-four healthy male rats were initially divided into 12-month-old and 24-month-old age groups (adult and older age groups, respectively; n = 12/group); subsequently, each age group was randomly divided into saline control (NS) and contrast media (CM) groups (n = 6/group). CM (76% diatrizoate, 10 mL/kg b.w.) was given through the caudal vein. Urinary creatinine (Ucr) and serum creatinine (Scr) were detected by an automatic biochemical analyzer. The activities of renal malondialdehyde (MDA), superoxide dismutase (SOD), angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) were determined by spectrophotometric assays with commercially available kits according to the manufacturers' protocols. Renal histological changes were observed by hematoxylin and eosin staining and scored semiquantitatively. RESULTS: In diatrizoate-injected aged rats, Scr, the activities of ACE, Ang II, MDA, and NADPH oxidase in renal tissues were significantly increased (p < 0.01). The histologic scores were higher in the aged animals with CM treatment than those of control or adult rats (p < 0.01). There was an increasing trend but no significant statistical difference in renal ACE, Ang II, MDA, and NADPH oxidase or histologic scores in adult CM-injected rats compared with control animals (p > 0.05). CONCLUSIONS: Older age is an aggravating factor of iodinated-contrast-media-induced nephropathy in male rats. Oxidative stress and the renin-angiotensin system (RAS) may play an important role in nephrotoxicity induced by iodinated contrast media, especially in aged male rats.

Epithelial-to-mesenchymal transdifferentiation of renal tubular epithelial cell mediated by oxidative stress and intervention effect of probucol in diabetic nephropathy rats.

OBJECTIVE: To elucidate the relationship of oxidative stress and specificity protein 1 (Sp1) in the process of epithelial-to-mesenchymal transdifferentiation (EMT) and also to investigate the molecular mechanism of protective effect of probucol on the pathogenesis of diabetic kidney disease (DKD). METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into control group, diabetic group, and diabetic group under probucol therapy (n = 10 per group). The biochemical indicators including 24-h urinary total protein (24-h UTP) excretion, blood glucose (BG), lipids [triglycerides (TGs), total cholesterol (TC)], serum creatinine (Scr), creatinine clearance rate (Ccr), kidney tissue malondialdehyde (MDA) level, and glutathione peroxidase (GSH-Px) activity were assessed in all groups. The renal pathological changes were evaluated by hematoxylin and eosin (HE) and Masson staining. The protein expression of Sp1, α-smooth muscle actin (α-SMA), and E-cadherin was also measured and analyzed by immunohistochemistry and Western blotting. RESULTS: Compared with the control group, the BG, TC, Scr, 24-h UTP, and MDA level of renal tissue increased significantly and the Ccr reduced in the rats of diabetic group (all p < 0.01). The pathological scores and the expression of Sp1 and α-SMA in renal tissue were up-regulated (p < 0.01) and the expression of E-cadherin was down-regulated significantly in the diabetic animals (p < 0.01). In the diabetic animals treated with probucol, the renal injuries were alleviated (p < 0.01). CONCLUSIONS: Oxidative stress may play an important role in the EMT process of tubular epithelial cells. Probucol could ameliorate renal disease progression in this model of diabetic nephropathy, which might be due to an antioxidant action, down-regulation of Sp1 protein expression, and inhibition of renal tubular EMT.