Effects of chronotherapy of benazepril on the diurnal profile of RAAS and clock genes in the kidney of 5/6 nephrectomy rats

Abstract

This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system (RAAS) and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy (STNx) were established. Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril group (MB) and evening benazepril group (EB). Benazepril was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.

Keywords

chronotherapy / benazepril / RAAS / circadian / clock genes / 5/6 subtotal nephrectomy

References

[1] OhdoS, KoyanagiS, MatsunagaN. Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock. Adv Drug Deliv Rev, 2010, 62(9–10): 885-897

[2] MehtaR, DrawzPE. Is nocturnal blood pressure reduction the secret to reducing the rate of progression of hypertensive chronic kidney disease?. Curr Hypertens Rep, 2011, 13(5): 378-385

[3] SmolenskyMH, HermidaRC, AyalaDE, et al.. Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension. Blood Press Monit, 2010, 15(4): 173-180

[4] OríasM, Correa-RotterR. Chronotherapy in hypertension: a pill at night makes things right?. J Am Soc Nephrol, 2011, 22(12): 2152-2155

[5] HermidaRC, AyalaDE, MojónA, et al.. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. J Am Soc Nephrol, 2011, 22(12): 2313-2321

[6] BălanH, PopescuE, AngelescuG. Comparing different treatment schedules of Zomen (zofenopril). Rom J Intern Med, 2011, 49(1): 75-84

[7] KurodaT, KarioK, HoshideS, et al.. Effects of bedtime vs. morning administration of the long-acting lipophilic angiotensin-converting enzyme inhibitor trandolapril on morning blood pressure in hypertensive patients. Hypertens Res, 2004, 27(1): 15-20

[8] KohnoI, IjiriH, TakusagawaM, et al.. Effect of imidapril in dipper and nondipper hypertensive patients: comparison between morning and evening administration. Chronobiol Int, 2000, 17(2): 209-219

[9] StergiouGS, NasothimiouEG. Does dosing antihypertensive drugs at night alter renal or cardiovascular outcome: do we have the evidence?. Curr Opin Nephrol Hypertens, 2008, 17(5): 464-469

[10] BidaniAK, GriffinKA, BakrisG, et al.. Lack of evidence of blood pressure-independent protection by renin-angiotensin system blockade after renal ablation. Kidney Int, 2000, 57(4): 1651-1661

[11] PortaluppiF, BagniB, degli UbertiE, et al.. Circadian rhythms of atrial natriuretic peptide, renin, aldosterone, cortisol, blood pressure and heart rate in normal and hypertensive subjects. J Hypertens, 1990, 8(1): 85-95

[12] VeglioF, PietrandreaR, OssolaM, et al.. Circadian rhythm of the angiotensin converting enzyme (ACE) activity in serum of healthy adult subjects. Chronobiologia, 1987, 14(1): 21-25

[13] HermidaRC, AyalaDE, FernándezJR, et al.. Administrationtime differences in effects of hypertension medications on ambulatory blood pressure regulation. Chronobiol Int, 2013, 30(1–2): 280-314

[14] PetersH, BorderWA, NobleNA. Targeting TGF-beta overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int, 1998, 54(5): 1570-1580

[15] FujiharaCK, VelhoM, MalheirosDM, et al.. An extremely high dose of losartan affords superior renoprotection in the remnant model. Kidney Int, 2005, 67(5): 1913-1924

[16] HouFF, XieD, ZhangX, et al.. Renoprotection of optimal antiproteinuric doses (ROAD) study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J Am Soc Nephrol, 2007, 18(6): 1889-1898

[17] KeYS, CaoH, YangT. Effect of combination of valsartan with benazepril on blood pressure and left ventricular hypertrophy in SHR. Acta Pharmacol Sin, 2000, 21(11): 1043-1047

[18] AmannK, SimonavicieneA, MedwedewaT, et al.. Blood pressure-independent additive effects of pharmacologic blockade of the renin-angiotensin and endothelin systems on progression in a low-renin model of renal damage. J Am Soc Nephrol, 2001, 12(12): 2572-2584

[19] MinoraDS, WaterhouseJM. Circadian rhythms of urinary excretion: The relationship between the amount excreted and the circadian changes. J Physiol, 1982, 327: 39-51

[20] WessonLG. Diurnal circadian rhythms of renal function and electrolyte excretion in heart failure. Int J Chronobiol, 1979, 6(2): 109-117

[21] CohnC, WebbL, JosephD. Diurnal rhythms in urinary electrolyte excretions by the rat: Influence of feeding habits. Life Sci, 1970, 9(14): 803-809

[22] ZuberAM, CentenoG, PradervandS, et al.. Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci USA, 2009, 106(38): 16523-16528

[23] StowLR, GumzML. The circadian clock in the kidney. J Am Soc Nephrol, 2011, 22(4): 598-604

[24] MonosíkováJ, HerichováI, MravecB, et al.. Effect of upregulated renin-angiotensin system on per2 and bmal1 gene expression in brain structures involved in blood pressure control in TGR(mREN-2)27 rats. Brain Res, 2007, 141180: 29-38

[25] HerichováI, MravecB, StebelováK, et al.. Rhythmic clock gene expression in heart, kidney and some brain nuclei involved in blood pressure control in hypertensive TGR(mREN-2)27 rats. Mol Cell Biochem, 2007, 296(1–2): 25-34

[26] BaltatuO, JanssenBJ, BriccaG, et al.. Alterations in blood pressure and heart rate variability in transgenic rats with low brain angiotensinogen. Hypertension, 2001, 37(2part2): 408-413

[27] CamposLA, Cipolla-NetoJ, AmaralFG, et al.. The Angiotensin-melatonin axis. Int J Hypertens, 2013521783

[28] NonakaH, EmotoN, IkedaK, et al.. Angiotensin II induces circadian gene expression of clock genes in cultured vascular smooth muscle cells. Circulation, 2001, 104(15): 1746-1748