21 Transgenie Animals
329
plasma concentration among hypertensive subjects, have been interpreted
as an inherited predisposition to the development of essential hypertension
(41). Interestingly, angiotensin-converting enzyme does not appear tobe
associated with hypertension in humans, but with myocardial infarction
in certain patients ( 42). This suggests that the RAS may not only be involved
in the elevation ofblood pressure, but also in the sequelae ofhypertension
such as cardiovascular end-organ disease. For renin, a restriction fragment
length polymorphism (RFLP) has been linked to hypertension in the Dahl
salt -sensitive rat ( 43 ), whereas no linkage could be demonstrated in humans
(44). To test the functional relevance ofthese genes in vivo, transgenic animals have been established. Initally a number of transgenic mouse lines
were established to express genes of the RAS, but transgenic rats have
been the species of choice more recently.
The first transgenic rat line in hypertension research was generated by
microinjection ofthe mouse Ren-2 gene (45) into oocytes ofnormotensive
rats, resulting in rats suffering from fulminant hypertension. In heterozygous rats of this line, blood pressure increased shortly after weaning at 5
weeks of age, and maximum values of about 240 mmHg were reached at 10
weeks of age ( 46). Homozygous animals develop even higher blood pressure
and exhibited a high mortality rate if not treated with angiotensin converting enzyme (ACE) inhibitors (46) or other anti-hypertensive medications.
Both, heterozygous and homozygous TGR(mREN2)27 rats exhibited a
marked gender related polymorphism with respect to blood-pressure,
with higher blood pressure in males, probably caused by the higher Ievel
of androgens and their stimulatory effect on tissue RAS. The highest expression ofthe Ren-2 genewas found in the adrenal gland, whereas the kidney
(which expresses highest Ievels of endogenous renin in rats) showed only
low renin Ievels, which were probably influenced by negative feedback mechanisms ( 47).
Hypertension in TGR(mREN2)27 rats is dependent on angiotensin
(ANG) II since treatment with low-dose ACEinhibitors or ANG II antagonists normalized blood pressure ( 46). Preliminary experiments ( 48) showed
that the animals were extremely sensitive to ANG II receptor (AT1) antagonists. The plasma RAS is not stimulated in this line and plasma inactive
renin (prorenin) is the only substance showing higher plasma concentration. The source of this prorenin is probably the adrenal gland, since bilateral adrenalectomy reduced plasma Ievels by 80%. Another observation emphasizes the role of the adrenal gland in hypertension: The urinary excretion of deoxycorticosterone, corticosterone and aldosteronewas elevated in
young TGR(REN2)27 animals during the phase of developing hypertension
but not in adult rats. ACTH treatment caused a dramatic increase in steroid
329
plasma concentration among hypertensive subjects, have been interpreted
as an inherited predisposition to the development of essential hypertension
(41). Interestingly, angiotensin-converting enzyme does not appear tobe
associated with hypertension in humans, but with myocardial infarction
in certain patients ( 42). This suggests that the RAS may not only be involved
in the elevation ofblood pressure, but also in the sequelae ofhypertension
such as cardiovascular end-organ disease. For renin, a restriction fragment
length polymorphism (RFLP) has been linked to hypertension in the Dahl
salt -sensitive rat ( 43 ), whereas no linkage could be demonstrated in humans
(44). To test the functional relevance ofthese genes in vivo, transgenic animals have been established. Initally a number of transgenic mouse lines
were established to express genes of the RAS, but transgenic rats have
been the species of choice more recently.
The first transgenic rat line in hypertension research was generated by
microinjection ofthe mouse Ren-2 gene (45) into oocytes ofnormotensive
rats, resulting in rats suffering from fulminant hypertension. In heterozygous rats of this line, blood pressure increased shortly after weaning at 5
weeks of age, and maximum values of about 240 mmHg were reached at 10
weeks of age ( 46). Homozygous animals develop even higher blood pressure
and exhibited a high mortality rate if not treated with angiotensin converting enzyme (ACE) inhibitors (46) or other anti-hypertensive medications.
Both, heterozygous and homozygous TGR(mREN2)27 rats exhibited a
marked gender related polymorphism with respect to blood-pressure,
with higher blood pressure in males, probably caused by the higher Ievel
of androgens and their stimulatory effect on tissue RAS. The highest expression ofthe Ren-2 genewas found in the adrenal gland, whereas the kidney
(which expresses highest Ievels of endogenous renin in rats) showed only
low renin Ievels, which were probably influenced by negative feedback mechanisms ( 47).
Hypertension in TGR(mREN2)27 rats is dependent on angiotensin
(ANG) II since treatment with low-dose ACEinhibitors or ANG II antagonists normalized blood pressure ( 46). Preliminary experiments ( 48) showed
that the animals were extremely sensitive to ANG II receptor (AT1) antagonists. The plasma RAS is not stimulated in this line and plasma inactive
renin (prorenin) is the only substance showing higher plasma concentration. The source of this prorenin is probably the adrenal gland, since bilateral adrenalectomy reduced plasma Ievels by 80%. Another observation emphasizes the role of the adrenal gland in hypertension: The urinary excretion of deoxycorticosterone, corticosterone and aldosteronewas elevated in
young TGR(REN2)27 animals during the phase of developing hypertension
but not in adult rats. ACTH treatment caused a dramatic increase in steroid