Disturbances of circadian rhythm of blood pressure and local cardiac clock genes in nephrotic rats / 中华肾脏病杂志

ABSTRACT

Objective To observe the circadian blood pressure (BP) rhythms and the phase of heart circadian gene expression in adriamycin (ADR)-induced nephropathy rats,thus exploring the effect of circadian systems on circadian BP variation in nephrotic rats.Methods Sprague-Dawley (SD) male rats (8 weeks) were housed in a 12∶12 hour light/dark cycle in two weeks,and randomly divided into ADR group and control group.ADR rats were injected 6.5 mg/kg adriamycin via vein to establish nephrotic rats model two weeks later,while control rats were injected the equal volume of saline.Five rats in each group were implanted with the radio-telemetry into abdominal aortic.After seven days,systolic blood pressure (SBP),diastolic blood pressure (DBP),mean arterial pressure (MAP) and heart rate (HR) were recorded every one minute during 72 hours via radio-telemetry.Three rats in each group were sacrificed in six time points (zeitgeber time=0200,0600,1000,1400,1800,2200) to get the blood sample and heart tissue,respectively.The mRNA expressions of core clock gene CLOCK,BMAL1,Per1,Per2,Cry1 and Cry2 in heart issue were evaluated by the real-time quantitative PCR.The plasma levels of renin activity angiotensin Ⅱ and aldosterone were measured by radioimmunoassay.All the data were analyzed by a partial Fourier analysis and stepwise regression.Results (1) There was no significant difference in 24 h average of SBP,DBP and MAP between two groups.In control group,there was higher SBP (3.22 mmHg),DBP (1.16 mmHg) and MAP (3.19 mmHg) in dark period than those in light period,only SBP and MAP showing statistical difference (all P ＜ 0.05).However,SBP,DBP and MAP had no significant difference between dark and light in ADR group (all P ＞ 0.05).(2) Control rats had (8.0+24.0) h rhythm of SBP,and their DBP,MAP and HR appeared 24.0-hour normal circadian pattern (all P ＜ 0.05).In ADR group,the rhythm of SBP completely disappeared.And their DBP and MAP remained 24.0 h circadian rhythm,but the peak time advanced 1.5 h to 3.0 h compared with SD rats.(3) In SD controls,daily rhythms period of the core clock genes (CLOCK,BMAL1,Cry1,Cry2,Per1 and Per2) mRNA expression in the heart were (4.8+ 12.0) h,24.0 h,12.0 h,(12.0+24.0) h,(4.8+12.0) h and 12.0 h (all P ＜ 0.05),respectively.In ADR rats,the rhythm of CLOCK,BMAL1,Cry2,Per1 and Per2 mRNA completely disappeared (all P ＞ 0.05).The circadian rhythm of Cry1 mRNA remained,but the period was changed from 12.0 h to (4.8+6.0) h.(4) The plasma renin and aldosterone concentration presented 12.0 h and 24.0 h daily rhythms in SD rats (all P ＜ 0.05).These diurnal changes however completely disappeared in ADR rats (all P ＞ 0.05).Conclusions ADR nephrotic rats lose the circadian rhythm of BP with the disturbances of cardiac circadian clock system.The disrupted diurnal rhythm of the core clock genes (CLOCK,BMAL1,Cry2,Per1 and Per2) mRNA expression in the heart may regulate the pathological circadian rhythms of heart tissue,which is involved with disturbances of circadian rhythm of BP.