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The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both

in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The
increased RAAS activity plays an important role in the hemodynamic and
nonhemodynamic pathogenetic mechanisms involved in kidney disease. Previous studies
have demonstrated that albuminuria is not only a marker of glomerular lesions, but also a
progression promoter, and finally a powerful predictor of the long-term beneficial effect of
blood pressure-lowering therapy. Randomized crossover and parallel blind studies in
patients with diabetic nephropathy have demonstrated that angiotensin II receptor blockers
(ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and
proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition.
Studies have revealed the optimal renoprotective dose for some ARBs; however, additional
dose titration studies are urgently needed to obtain the maximum benefit of this valuable
new class of compounds. The combination of ARB and ACE inhibition is well tolerated
and even more effective than monotherapy in reducing systemic blood pressure and
albuminuria in diabetic nephropathy. In addition, dual RAAS blockade is safe and well
tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with
some blood pressure-lowering agents implies disturbances in the downstream transmission
of the systemic blood pressure into the glomerulus, leading to capillary hypertension or
hypotension depending of the level of blood pressure. ARB does not interfere with GFR
autoregulation in hypertensive diabetic patients. In contrast to previous observational
studies with ACE inhibition, long-term treatment with ARB has similar beneficial
renoprotective effect on progression of diabetic kidney disease in hypertensive diabetic
patients with ACE II and DD genotypes. ARB can prevent/delay development of diabetic
nephropathy independently of its beneficial blood pressure-lowering effect in patients with
type 2 diabetes and microalbuminuria. Recently, two landmark studies led to the following
conclusion: Losartan and Irbesartan conferred significant renal benefit in patients with
type 2 diabetes and nephropathy. This protection is independent of the reduction in blood
pressure it causes. The ARB is generally safe and well tolerated. A recent metaanalysis
indicates that ARBs reduce cardiovascular events mainly because of reduction in first
hospitalization for congestive heart failure in hypertensive type 2 diabetic patients with
albuminuria. The studies mentioned here suggest that ARB represents a beneficial
treatment of hypertension and proteinuria in incipient and overt diabetic nephropathy.

The effect of ARB in diabetic nephropathy

The increased activity of the reninangiotensinaldosterone system (RAAS) is an
important pathogenetic factor in the development of nephropathy in diabetic patients. The
damaging factor of this system is the end-product, angiotensin II, and the damaging effects
are vasoconstriction, increase of aldosterone secretion, growth, fibrosis, thrombosis,
inflammation and oxidation. Theoretically, on this basis, blockade of the RAAS should
have a beneficial effect on the development of diabetic nephropathy. The main goal in the
treatment of diabetic nephropathy is control of the glycaemic status and aggressive
antihypertensive therapy, primarily with RAAS-blocking agents. It was demonstrated
recently that angiotensin II receptor blockers (ARBs) have a slowing effect on the
progression of diabetic nephropathy (RENAAL and IDNT trials) or on the development of
proteinuria (IRMA) in type 2 diabetes. These effects are specific and independent of the
decrease in blood pressure. Theoretically, the combination of an angiotensin-converting
enzyme inhibitor (ACEI) and an ARB can lead to a more complete blockade of the RAAS.
A new study (ONTARGET) has now started to investigate whether treatment with a
combination of an ACEI and an ARB has a more potent beneficial effect on the
cardiovascular events and the nephropathy in type 2 diabetic patients as compared with
separate treatment with the two agents.
Five years ago, it was estimated that 151 million people worldwide had diabetes mellitus,
almost 97% of these cases being type 2 diabetes [1]. It is also recognized that an increasing
number of patients reach end-stage renal disease (ESRD) due to diabetic nephropathy,
which is the leading cause of ESRD [2].
The natural history of type 1 and type 2 diabetic nephropathy is similar with regard to the
progression from microalbuminuria to proteinuria [3]; however, the contribution of various
factors to the pathophysiology is somewhat different between the two types of diabetes.
Among these factors should be mentioned hyperglycaemia and hypertension.
The principal aim in the treatment of diabetic nephropathy is control of the glycaemia and
aggressive antihypertensive therapy, decreasing the blood pressure (BP) below 130/85
mmHg [4]. The question is what antihypertensive therapy should be used.

At first sight, it might seem paradoxical to treat diabetic nephropathy by inhibition of the
reninangiotensinaldosterone system (RAAS), because the blood renin levels in diabetic
subjects are low rather than high [5].
RAAS and its blockade in diabetic nephropathy
Recent human and experimental studies have revealed that there is an increased local
activity of the RAAS and an increased production of angiotensin II (Ang II) in the kidney
[5]. Ang II has known cardiovascular and renal-damaging effects: vasoconstriction,
increase in aldosterone secretion, growth, fibrosis, thrombosis, inflammation and
oxidation, which are mediated by the angiotensin AT1 receptor [6]. Consequently,
prevention of the effects of Ang II mediated by the AT1 receptor seems to have a beneficial
effect on the progression of diabetic nephropathy [7]. It was demonstrated earlier that
blockade of the RAAS by angiotensin-converting enzyme inhibitors (ACEIs) can have a
beneficial effect on the progression of diabetic nephropathy [8]. This specific
nephroprotective effect may be explained by the vasodilatating effects of ACEIs on the
glomerular efferent arterioles. Clinical trials have confirmed the beneficial effect of these
treatments: ACEIs decreased the proteinuria and attenuated the progression of the renal
disease in diabetic subjects [9]; however, according to other published data, ACEIs were
not superior to other antihypertensive agents in slowing down the progression of type 2
diabetic nephropathy [10].
Angiotensin receptor blockers (ARBs) represent a new class of antihypertensive drugs that
block the RAAS. They selectively block the AT1 receptor and in this way inhibit the
vasoconstrictive and tissue-damaging effects of Ang II in diabetes, including growth,
inflammation and thrombosis.
Trials with AT1 receptor blockers in type 2 diabetic nephropathy
Three trials recently have studied the ARBs in patients with diabetic nephropathy.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan
(RENAAL) study investigated the effects of the ARB, losartan, in 1513 patients with type
2 diabetes and nephropathy [11]. In this study, which lasted for 3.4 years, one group
received losartan, while the other group received conventional antihypertensive agents
(placebo group). The target BP was <140/90 mmHg. The main question was whether the
treatment with losartan could influence the primary end-point (the composite of death,

ESRD and doubling of serum creatinine) and the secondary end-points (composite of
morbidity and mortality from cardiovascular causes, proteinuria and the rate of progression
of the renal disease).
Losartan reduced the relative risk of the primary composite end-point as compared with the
placebo group by 16% (P < 0.02), reduced the incidence of doubling of serum creatinine
by 25% (P < 0.006) and reduced ESRD by 28% (P < 0.02). The proteinuria was also
significantly decreased. Extrapolating from the observed data, this reduction corresponds
to an average delay of 2 years in the need for dialysis or transplantation as estimated by the
authors. There was no significant difference in relation to the risk of death, or
cardiovascular morbidity and mortality.
The Irbesartan Diabetic Nephropathy Trial (IDNT) investigated the effects of irbesartan
and amlodipine on the rate of progression of diabetic nephropathy in 1715 subjects with
type 2 diabetic nephropathy [12]. The duration of the study was a mean of 2.6 years. The
first group was treated with irbesartan, the second with amlodipine and the third with
conventional antihypertensive drugs (placebo group). It was planned to achieve a BP goal
of <135/85 mmHg. The primary and secondary end-points were very similar to those in the
RENAAL study.
Irbesartan demonstrated a relative risk (RR) reduction vs placebo by 20% of the composite
end-point (P < 0.02), by 33% of the doubling of serum creatinine (P < 0.003) and by 23%
of ESRD (P < 0.07). Irbesartan displayed an even more significant RR reduction vs
amlodipine, by 23% of the composite end-point (P < 0.006), and by 37% of the doubling of
serum creatinine (P < 0.001). In this comparison, the incidence of ESRD was on the
borderline of significance, vs both the placebo and amlodipine. The ARB treatment
significantly decreased the proteinuria. The RR of death, cardiovascular morbidity and
mortality was not significantly changed in either comparison.
Not only the design of the two studies with ARBs (RENAAL and IDNT), but also the
results were very similar. From these data, we realized that the more beneficial
nephroprotective effect of the ABRs starts to differ from that of conventional therapy only
after 1.5 years and that the difference becomes significant later. There are minor
differences between the results of the RENAAL and IDNT studies. Regarding the
incidence of ESRD, this was decreased in both studies, but the decrease was not significant

in the IDNT study. Considering that the duration of the IDNT study was shorter (2.6 years)
than the RENAAL study (3.4 years), we could assume that, if the IDNT study had lasted
longer, the decrease in ESRD would have been significant. The highly significant RR of
doubling of the serum creatinine supports this assumption. From the above-mentioned data,
we can conclude that to study the effect of a therapy on diabetic nephropathy, the trial
should be designed to last longer (probably not less than 3.54 years).
Both the RENAAL and the IDNT study have shown that losartan and irbesartan have
specific nephroprotective effects, independently of the BP reduction. These results indicate
that the ARBs have an important role in the management of patients with type 2 diabetic
The third trial, IRbesartan MicroAlbuminuria in hypertensive patients with type 2 diabetes
(IRMA 2), was carried out in 520 subjects with type 2 diabetes, who were followed for 2
years [13]. The patients had persistent microalbuminuria and a normal renal function. One
group of patients received irbesartan, while the placebo group was treated with
conventional antihypertensive agents to achieve the target BP of <135/85 mmHg.
The primary end-point was the time of development of diabetic nephropathy. Irbesartan
revealed a 39% RR reduction vs placebo in the development of nephropathy (P < 0.001).
This study confirmed that the ARB, irbesartan, has a specific antiproteinuric effect. The
question still remains of how much this treatment can prevent the development of diabetic
As previously discussed, both the ACEIs and ARBs have a specific nephroprotective effect.
Since Ang II may be produced through other pathways, involving enzymes other than ACE
(e.g. chymase), it would be worthwhile to investigate whether the combination of an ACEI
and an ARB with a theoretically more extensive blockade of the RAAS would have a more
efficient nephroprotective effect than the two agents alone.
The worldwide largest (n = 28 400) trial to date is the Ongoing Telmisartan Alone in
combination with Ramipril Global Endpoint Trial (ONTARGET). This trial recently started
in type 2 diabetic patients, to investigate the effects of combined ACEIARB therapy. The
patients will be treated randomly with telmisartan or ramipril separately and with a

combination of the two agents. In addition to the primary composite (of cardiovascular
death) and secondary end-points, the occurrence of nephropathy will be investigated.
Experience in the recent past indicated that the most successful strategy for the treatment
of diabetic nephropathy is the inhibition or blockade of the RAAS, using ACEIs or ARBs
Many studies suggest promising steps in the development of therapeutic approaches to
prevent or to decrease the rate of progression of type 2 diabetic nephropathy. The recently
published data from many trials suggest that the antihypertensive ARB agents have a
slowing effect on the progression of diabetic nephropathy and on the development of
proteinuria in type 2 diabetes. Accordingly, ARBs are useful to treat type 2 diabetic



AT1 receptor





administration of the AT1 antagonist candesartan blocks brain AT1 receptors and
prevents the hormonal and sympathoadrenal response to isolation stress.

To determine whether or not Ang II and AT1 receptors played significant roles in
the regulation of the stress reaction, we studied the response of the organism to
stress a f t e r s u s t a i n e d b l o c k a d e o f p e r i p h e r a l a n d b r a i n A T 1
r e c e p t o r s . We f i r s t d e v e l o p e d a n a n i m a l m o d e l o f b r a i n AT1 receptor
blockade after peripheral administration of the receptor antagonist, a model necessary to
relate our findings i n a m e a n i n g f u l w a y t o c l i n i c a l c o n d i t i o n s i n
h u m a n populations. We found that peripheral administration of a selective, potent,







a d m i n i s t e r e d f o r 2 w e e k s , significantly decreased AT1 r e c e p t o r b i n d i n g ,



i n peripheral tissues and circumventricular organs, but also inthe

hypothalamic paraventricular nucleus and in the nucleuso f t h e s o l i t a r y t r a c t ,









b a r r i e r . C h r o n i c peripheral administration of candesartan inhibits brain AT1

receptor binding to a higher degree than its acute peripheral administration[73]. T h i s
i n d i c a t e d a n u n s u s p e c t e d a n d excellent penetration of candesartan into the
brain, resulting at the higher doses used in an almost complete blockade of brain
AT1 receptors[72].W e t e s t e d t h e e f f e c t o f A T 1 receptor blockade with
candesartan administered for 2 weeks before submitting the animals to the stress of
isolation, a clinically relevant model r e s u l t i n g , i n r o d e n t s , f r o m t h e



surroundings and access to





familiar territory. Twenty-four hours of

isolation enhance AT1 receptor expression in the paraventricular nucleus (Fig.5)

[54]to an extent similar to the increase in AT1 receptors t h a t o c c u r s d u r i n g
r e p e a t e d immobilization stress[60], i n c r e a s e d p i tuitar y A C T , d e c r e a s e d
p i t u i t ary vasopressin[54]and increased













( Fig. 6),



catecholamine synthesis, hallmarks of the stress reaction[54](F i g s . 6 a n d

7 ). Pretreatment with candesartan blocked AT1 receptor binding after isolation
not only in peripheral tissues but also in the brain, in a manner similar to
that previously observed in unstressed animals (Fig. 5)[54],prevented the
increase in pituitary ACTH and adrenal corticosterone and the decrease in


(F i g .






adrenomedullary catecholamine response, including the isolation-induced

increase in tyrosine hydroxylase transcription, and decreased the urinary

excretion of catecholamines, corticosterone and vasopressin [54](Fig. 7). Our
results demonstrated that simultaneous antagonism o f p e r i p h e r a l a n d
b r a i n AT1 receptors could represent an advantage in the control of the stress
reaction. If blockade of pathologically enhanced responses to stress has beneficial








c a n d e s a r t a n c o u l d h a v e a p l a c e i n t h e t h e r a p y o f stress-related disorders.
Effect of pretreatment with candesartan on an acute stress induced disorder
To establish whether or not AT1 receptor blockade could be of therapeutic benefit, we
initiated a study of the effects o f c a n d e s a r t a n o n t h e d e v e l o p m e n t


candesartan o n

disorders. We first





t h e incidence of gastric ulcers induced by cold-

restraint [74], a commonly used and clinically relevant e xperimental model

for acute stress-induced gastric damage [75]. Stress induces acute gastric
mucosa lesions by a variety of mechanisms, including psychological factors
influencing individual vulnerability, stimulation of specific brain path-ways
regulating autonomic function, decreased blood flow to the mucosa,










radical generation

resulting in increased lipid peroxidation [7679]. Maintenance of gastric

blood flow is important to protect the mucosa from endogenous and exogenous






AT 1

receptor stimu l a t i o n , i n c r e a s e s v a s c u l a r t o n e i n r e s i s t a nce arteries

[80]including those of the gastric vasculature [81]leading to decreased blood
flow and ischemia. We speculated that AT1 r e c e p t o r i n h i b i t i o n w i t h
c a n d e s a r t a n c o u l d p r o t e c t gastric blood flow during stress and reduced
gastric ulcer formation. We found that candesartan dramatically decreased







s t r e s s , protecting the g a s t r i c m u c o s a f r o m s t r e s s - i n d u c e d i n j u r y (Fig.

8)[74]. Several interrelated mechanisms are probably i n v o l v e d



p r o t e c t i v e e f f e c t o f t h e AT1 antagonist,including the reduction of the

stress-induced adrenomedullary catecholamine formation and release, increase in

gastric blood flow and anti-inflammatory effects[74]. The protect i o n








A T 1 receptor

antagonists is probably mediated by inhibition of receptors localized to the

endothelium of arteries located in the gastric mucosa[74]and is similar to the
protective effect on cerebral blood flow during brain ischemia [82,83].We













factor a


(TNF-a) ,


adhesionm o l e c u l e - 1

( I C A M - 1 ) a n d t h e number of infiltrating neutrophils in the gastric

mucosa (Fig. 8)[74], which play c r u c i a l r o l e s i n t h e p r o g r e s s i o n o f

i n j u r y [84]. Activated neutrophils release inflammatory mediators

capable of damaging endothelial cells and inhibition of neutrophil infiltration prevents

the stress-induced reduction of mucosal flow and the production of gastric
lesions[85]. Ang II promotes tissue inflammation; enhancing neu trophil


A T 1 r e c e ptor stim u l a t i o n [ 8 6 , 8 7 ] increased

expression of TNF-a [8689],ICAM-1[90]and P-selectin[91]. We demonstrated that

pretreatment with the AT1 antagonist decreased the stress-induced overexpression of
TNF-a and ICAM-1 overexpression and the neutrophil infiltration in the
gastric mucosa indicating that the anti- inflammatory effects of AT1 blockade
could be relevant for the protection of stress-induced lesions ( Fig. 8)
[74].These results show that inhibition of AT1 receptors, by combined local
and systemic mechanisms, protects gastric blood flow inhibits the pro inflammatory
cascade preventing the gastric ischemia and inflammation characteristic of a
major stress r e s p o n s e a n d p r o t e c t i n g t h e g a s t r i c m u c o s a f r o m
s t r e s s - induced ulcerations.AT1 b l o c k a d e d i d n o t p r e v e n t t h e i n c r e a s e i n
adrenalc o r t i c o s t e r o n e p r o d u c e d b y c o l d - r e s t r a i n t a s i t d i d
i n response to isolation[53,74]. This demonstrated that Ang II regulates
the stress reaction differently depending on the k i n d a n d i n t e n s i t y
o f t h e s t r e s s . P r e s e r v a t i o n o f t h e glucocorticoid response





c a n d e s a r t a n , b e c a u s e c o r t i c o i d s have





been proposed to protect

a g a i n s t g a s t r i c u l c e r a t i o n [92]. Thus, our experiments demonstrate a

clear protective anti-stress effect of candesartan in an acute stress-induced