1. Mice heterozygous for an Ins2 mutation (Akita mice) develop severe insulin-dependent diabetes mellitus and have been used by us and others as a mouse model to study diabetic nephropathy. Because of the critical role of blood pressure in causing end-organ damage we determined long-term blood pressure (MAP) and heart rate (HR) levels, their circadian variability, and their regulation by changes in salt intake in diabetic Akita and wild type mice by using the radiotelemetry system in unrestrained animals at about 12 weeks of age. Akita mice demonstrated robust circadian rhythms of mean arterial, systolic and diastolic blood pressure, heart rate and locomotor activity without significant differences in the mesor, amplitude, and acrophase of the rhythms compared with C57BL/6J mice. However, 24-h mean heart rate was significantly lower in Akita mice compared with C57BL/6J mice (527 10 vs. 581 14 bpm;p=0.008), especially in the dark period. After obtaining baseline values the mice were placed on diets with either a high (8.0%) or low (0.04%) NaCl content in a random order. All diets were provided for a 1-wk period prior to the 7 day telemetry study. Both Akita and C57BL/6J mice adapted to the low NaCl diet without significant changes of the rhythm parameters and the mean values of blood pressure and locomotor activity although blood pressure tended to be lower in Akita reaching significance for systolic pressure values. On the high NaCl diet, Akita mice showed a striking further reduction in heart rate in both light and dark phases (489 12 vs. 571 10 bpm, p=0.001), and the appearance of a second heart rate and blood pressure minimum at 2 AM. We conclude that circadian patterns of blood pressure, heart rate and locomotor activity are not dramatically altered in 12-week old Akita diabetic mice with established diabetes mellitus. However, reduced heart rates in response to a high salt diet and reduced blood pressures during low NaCl diet suggest a regulatory impairment in type 1 diabetes, presumably at the level of the autonomic nervous system and baroreflex functions. 2. Light is well known to serve as the strongest input for the entrainment of circadian rhythms of locomotor activity, body temperature, and cardiovascular functions. However, food intake has also been shown to independently entrain locomotor activity, but less is known whether food also affects blood pressure rhythmicity. We have therefore assessed the ability of the food cue to determine circadian variations of renal and cardiovascular functions. In experiments in wild type mice food was offered during the daytime (between 10 AM and 2 PM) for 6 consecutive days under 12 hr light (6 to 18 hr):12 hr dark conditions (18 to 6 hr). During ad libitum feeding (AL) food was always available. Blood pressure and heart rate were determined by radiotelemetry for 20 consecutive days (7 day AL, 6 days RF, 7 days AL). Urine was collected in metabolic cages in 4 hr periods;urinary Na and K were determined with flame photometry. GFR was measured by single injection FITC inulin clearance at two time points (12 and 24 hr). On the normal ad libitum feeding pattern, blood pressure, heart rate and activity peaks occurred during the active night period (acrophases at 0:050:05, 23:100:21 and 22:440:17, respectively). Restricted daytime feeding caused a dramatic phase shift to the light period (acrophases at 14:380:43, 13:400:33 and 16:310:33, respectively;p<0.01). During AL peaks of water, Na and K excretion were seen between 19 and 23 hrs (49296 l/4h, 9419 mEq/4h, 15733 mEq/4h). After 6 days of restricted feeding, peaks of water and K excretion occurred in the period 11-15 hrs (737109 l/4h, 17028 mmol/4h) while the urinary Na peak was observed in the 15-19 hr period (1069 mmol/4h;p<0.001). During AL GFR at midnight and noontime were not significantly different (39332l/min vs 36110 l/min, p=0.204). After 6 days of RF, GFR at midnight was significantly lower at noontime (23341l/min vs. 39332l/min, p=0.0193). Clock genes (Bmal1, Per1, Cry1, Clock) in both liver and kidney showed a significant phase shift with the restricted daytime feeding protocol. Expression of NHE3, AQP2, V1aR, renin and NKCC1 mRNA showed circadian variation (one way ANOVA, p<0.01), and a phase advance after 6 days of daytime feeding (p<0.01, two way ANOVA). Expression of Oct1, Oct2, NKCC2, NCC and ENac did not show significant circadian variations, and RF did not change expression levels. We conclude that food intake causes a marked and rapid adaptation of cardiovascular and renal circadian variations. The resetting of expression of clock genes and clock-controlled genes in the kidney during daytime feeding may be related to the temporal resetting of kidney function.
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| Kim, Soo Mi; Power, Andrea; Brown, Timothy M et al. (2009) Deletion of the secretory vesicle proteins IA-2 and IA-2beta disrupts circadian rhythms of cardiovascular and physical activity. FASEB J 23:3226-32 |
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