Calorie Restriction Prevents Contrast-induced Acute Kidney Injury In Rats Via SIRT1

BackgroundIodine contrast agent is a kind of drugs commonly used for diagnostic angiography and interventional treatment of cardiovascular,but the happen of contrast-induced acute kidney injury(CI-AKI)has been associated with an increased risk of angiography and interventional therapy,particularly limited part of patients with the original renal damage to implement angiography and interventional treatment.According to statistics,CI-AKI has become the third major causes of iatrogenic acute renal insufficiency,increased hospital mortality and dialysis rate.Although previous studies have found that some compounds can protect CI-AKI,but in addition to angiography before and after hydration therapy has been shown to have a protective effect,there is no recognized effective means of prevention and treatment of CI-AKI.Due to the use of iodine contrast agent is inevitable,it has important clinical significance to develop drugs preventing and treating CI-AKI.Calorie restriction(CR)is one kind of diet control method by reducing the total calorie intake,but avoiding the occurrence of malnutrition.Since 1930 s,the role of caloric restriction in delaying aging and reducing age-related organ damage has been recognized widely.It is now recognized as a means of prolonging life in lower organisms such as yeast and fruit flies,rodents and primates.With the deepening of researches in recent years,the role of caloric restriction has been extended to the protection of multiple organs and disease model.The study found that caloric restriction has protective effects on a variety of k idney diseases such as aging related renal injury,diabetic nephropathy,renal ischemia-reperfusion injury,and cisplatin induced renal injury.The study found that a variety of renal protective effects of caloric restriction are related with silent information regulator 1(SIRT1).SIRT1 is a deacetylase which dependent on nicotinamide adenine dinucleotide(NAD+),regulates apoptosis,autophagy,metabolism of cell by controlling gene silencing through multiple receptor protein acetylation.The contrast agent circulated into the renal with the blood,caused hypoxia ischemia and oxidative stress injury of renal medulla tubular epithelial cells.This is the central link of CI-AKI pathogenesis.Because previous study found that CR can play the role of anti oxidative stress and anti apoptosis in the kidney,so we speculated that CR has protective effects on CI-AKI via SIRT1.Meanwhile,the related research has not been reported,so we design this topic.ObjectivesThe aim of the study was to observe the effect of CR on CI-AKI in rats and to explore its mechanism.MethodsClean and healthy SD rats(male and female,10 to 12 weeks,body weight 230 ±15g),were randomly divided into two groups.A group take food freely(AL group),the other group(CR group)were given 60% normal daily feeding for 4 weeks.All rats take water freely.Then,according to different administration,all rats were subdivided into 7 groups: vehicle group,simple caloric restriction group(CR group),contrast-induced acute kidney injury model group(CM group),contrast-induced acute kidney injury model with caloric restriction pretreatment group(CR+CM group),contrast-induced acute kidney injury model with the inhibitor and calorie restriction pretreatment group(EX527+CR+CM group),contrast-induced acute kidney injury model with resveratrol pretreatment group(RES+CM group),contrast-induced acute kidney injury model with the inhibitor and resveratrol pretreatment group(EX527+RES+CM group),5 rats in each group.To establish rat CI-AKI model,indomethacin,Nω-nitro-L-arginine methylester hydrochloride(L-NAME)and Iopromide were sequentially injected into rats via the left external jugular vein through a indwelling tube.EX527 and resveratrol were intraperitoneally 30 min before the injury.Th e rats were kept in metabolic cages for 24 h urinary collections after the injury.Then,the rats were killed.The samples of blood were collected from the abdominal aorta to measure serum creatinine(Scr)and blood urea nitrogen(BUN).The urine creatinin e(UCr)was measured to calculate creatinine clearance rate(CCr)according to the formula.The pathological changes of the kidney were observed and graded under HE staining.The level of renal tubular apoptosis was observed by TUNEL kits and reflected fro m the expression of cleaved caspase-3 by Western blot.The contents of malondialdehyde(MDA),superoxide dismutase(SOD),myeloperoxidase(MPO),IL-1β in kidney were measured by commercial kits to examine the changes of oxidative stress and inflammation.The expression of silent information regulator 1(SIRT1)in kidney was measured by Western blot.ResultsCalorie restriction pretreatment can significantly improve the renal function of rats with contrast-induced acute kidney injury,and significantly reduce the level of serum creatinine and blood urea nitrogen,increase creatinine clearance,ameliorate renal pathological damage.Meanwhile,Caloric restriction can reduce the renal cell apoptosis,decrease the expression level of Cleaved Caspase-3,decrease the level of MDA,increase the activity of SOD,decrease the content of MPO and IL-1β.The expression of SIRT1 protein in rat kidney tissue of contrast-induced acute kidney injury model group decreased,while calorie restriction pretreatment can improve the trend.The use of SIRT1 specific inhibitor EX527 can partially block the protective effect of caloric restriction on contrast-induced acute kidney injury.Resveratrol,a SIRT1 agonist,can be used to simulate the effects of caloric restriction on rats with contrast-induced acute kidney injury.ConclusionCaloric restriction can prevent contrast-induced acute kidney injury in rats by anti apoptosis,anti oxidative stress and anti inflammation,which may be related to the up regulation of SIRT1 protein expression in rat kidney.