Transgenic TGR(mREN2)27 rats as a model for disturbed circadian organization at the level of the brain, the heart, and the kidneys.
In transgenic hypertensive TGR(mREN2)27 rats (TGR) harboring the murine Ren-2 gene an inverse 24h blood pressure (BP) profile was described in relation to a normal pattern in heart rate (HR) and motility (MA), normotensive Sprague-Dawley rats (SDR) were used as controls. Transgenic rats as an animal model of human secondary hypertension (non-dipper) was studied in detail at different levels: (1) Radiotelemetry was applied to document gross circadian rhythms/rhythm disturbances in cardiovascular functions, MA and body temperature under normal LD conditions, under DD and after a light pulse. (2) Signal transduction of the overexpressed renin-angiotensin in TGR was studied by determation of AT1-receptors in kidney glomeruli together with kidney functions. (3) Expression of key processes involved in increased sympathetic regulation in TGR, mRNAs, the tyrosine-hydroxylase (TH) and norepinephrine (NE) reuptake1-carrier were determined. (4) In the SCN mRNA of c-fos and c-jun were determined under LD and after light pulse. (5) In primary cultures of pinealocytes the effects of adrenergic agonists and antagonists were evaluated on second messenger (cAMP, cGMP) accumulation and melatonin release. The results of these studies clearly demonstrate that the additional mouse renin genin in TGR greatly affected not only the renin-angiotensin-system and led--as expected--to an increased BP in this rat but also disturbed circadian rhythms from the BP pattern down to the level of hormones, processes of signal transduction, and expression of transcription factors and clock genes. In conclusion, the expression of a single additional gene is able to disturb the circadian system of an animal in a highly complex way. These findings are importance for chronobiologic as well as pharmacologic research.
Lemmer
Björn
B
Institute of Pharmacology and Toxicology, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany. bjoern.lemmer@urz.uni-heidelberg.de
Witte
Klaus
K
Enzminger
Helene
H
Schiffer
Sabine
S
Hauptfleisch
Stefan
S
D000375:Aging / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000502:physiology; D001831:Body Temperature; D001921:Brain / Q000503:physiopathology*; D002940:Circadian Rhythm / Q000502:physiology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000528:radiation effects; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D008027:Light; D008297:Male; D008550:Melatonin / Q000378:metabolism; D051379:Mice; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000502:physiology / Q000528:radiation effects; D027981:Symporters / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; C473112:Ren2 protein, mouse; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; D027981:Symporters; D014446:Tyrosine 3-Monooxygenase; D011493:Protein Kinase C; D012083:Renin; D008550:Melatonin