1. Activation of the Intrarenal Renin-
Angiotensin System is the Dominant
Contributor to Systemic Hypertension
POINT COUNTERPOINT
Prepared by Shraddha Shah (20309419)
KIN 470 Exercise Physiology Seminar
University of Waterloo
Monday, July 30, 2012

2. KIN 470 Point: Counterpoint Shraddha Shah
COUNTERPOINT: Activation of the Intrarenal Renin-Angiotensin System is the
Dominant Contributor to Systemic Hypertension
Hypertension is characterized by sustained high
blood pressure (BP). It is clinically accepted as a major
risk factor for cardiovascular diseases, which is the
current leading cause of morbidity and mortality (2, 7).
Although it is a modifiable risk factor (2), according to
the World Health Organization statistics of 2012,
hypertension is slowly but steadily becoming an
epidemic, affecting a third of the world’s adult
population (3). Due to its asymptomatic progression,
this condition is often called ‘the silent killer’ (7).
A healthy individual’s normal BP ranges between
a systolic pressure (SBP) of 90 – 120 mmHg and a
diastolic pressure (DBP) of 60 – 80 mmHg.
Pathologically, hypertension is defined as a value equal
to or exceeding a SBP of 140 mmHg and/or DBP of 90
mmHg. The term ‘systemic hypertension’ refers to a
sustained increase in arterial blood pressure (7).
There are two manifestations of hypertension:
essential (primary) and secondary. Secondary
hypertension, a condition recognized from known
causes, affects only 5 to 10 percent of the hypertensive
population, who undergo therapeutic treatments to
normalize blood pressure. However, 90 to 95 percent
of the patients fall under the former category, which is
idiopathic in nature (7). Since essential hypertension
affects majority of the afflicted population, it is
imperative to examine the mechanism that heavily
contributes to its development and progression: the
renin-angiotensin system (RAS).
Blood pressure is affected by changes in vascular
resistance and blood volume. One of the major organs
that releases endocrine hormones to modulate both
blood volume and resistance is the kidney (1, 2, 5, 6,
10). Along with its function to remove toxic wastes as
well as maintain sodium and water balance, the kidneys
play a vital role in long term BP regulation via RAS
(8).
In response to abnormally low blood pressure
(hypotension), reduced sodium delivery and
sympathetic stimulation, the juxtaglomerular apparatus
(JGA) of the kidneys release enzyme renin into
circulation (2, 5, 8, 10). Renin then binds to its
substrate angiotensinogen (AGT), secreted by the liver,
and is converted to its inactive form angiotensin I (AT
I). Via angiotensin converting enzyme (ACE) located
in the lungs, AT I is converted to angiotensin II (AT
II), the active form which has six downstream effects
to upregulate BP to normal (4). These include
myocardial hypertrophy, sympathetic vasoconstriction,
increased thirst, independent retention of sodium and
water through AT I receptors, secretion of aldosterone
via adrenal gland and the release of antidiuretic
hormones (ADH) from the pituitary gland (8). The
latter two effects also function to preserve sodium and
water balance. Likewise, in individuals with excessive
sodium intake and hypertension, the release of renin by
the JGA is suppressed and subsequent inhibiting events
cause downregulation of BP to normal. This is
indicative of appropriate RAS inhibition through a
negative feedback loop. Since renin, AGT, AT I and
AT II are all released into the bloodstream, this
pathway is interchangeably referred to as plasma,
circulating or classic RAS (10).
The discovery of intrarenal RAS began in the
early 1970s (2), where gene expressions of renin, AGT
and ACE2 (a homologue of ACE) were also found
within kidney nephrons (10). This finding was
confirmed with specific studies that demonstrated
sustained hypertension in spite of normal JGA
suppression and low plasma renin concentration (9, 14,
16, 17). Since the state of hypertension ceased to
normalize with the inhibition of circulating RAS, this
suggested that tissue RAS – prominently intrarenal
RAS – may have a greater role in the development and
sustenance of hypertension (6, 9 – 17).
From its discovery to present day, the
inappropriate activation of intrarenal RAS has
consistently proven to induce hypertension. Many
experiments have been conducted to support the
notion: i) AT II-dependent hypertension, ii) 2-kidney,
1-clip Goldblatt, iii) biomarker in hypertensive
patients, iv) transgenic rat, v) the remnant kidney
model and vi) genetically overexpressed mice model
(2). This review will discuss four studies that emulate
the first three experimental models listed above. Of the
four, three animal experiments are completed using
rat/mice models and one human study collects data
from patient profiles. All experiments with invasive
procedures are performed on animal models for ethical
reasons. However, most research that exists pertaining
to this field implies that similar results can be expected
from human models.
In 2002, Zhuo et al. performed a two-week
experiment on rats to detect intrarenal accumulation of
AT II. Age-matched rats with similar blood pressures
were divided into control, experimental and treatment
groups. The experimental group was chronically
infused with AT II to induce hypertension using an
osmotic pump. The treatment rats were chronically
infused with AT II plus an angiotensin receptor blocker
(ARB) to refute the upregulating effects of AT II on
BP. Results showed significant accumulation of
intrarenal AT II amongst experimental rats compared
to control and treatment groups. For that reason, the

3. KIN 470 Point: Counterpoint Shraddha Shah
experimental group sustained hypertension despite
normal inhibition of circulating RAS, whereas the
other two groups maintained normal BP ranges. This
suggests that the intrarenal RAS has a positive
feedback loop (15), independent of classic RAS, which
senses high BP and continues to activate intrarenal AT
II to progress hypertension (17).
A similar experiment was conducted in 2009 by
Zhao and colleagues to examine sodium reabsorption
in hypertensive mice. Again, AT II infusions were used
to inspire hypertension in these models. Mice were
split into two groups: control and experimental.
Glomerular filtration rate (GFR), urinary sodium
velocity and SBP values were collected repeatedly over
two weeks. GFR is the rate at which the filtered fluid
passes through the tubules of the kidney. Similarly,
urinary sodium velocity is the rate at which sodium
flows through urine. Slower rates translate into greater
sodium reabsorption capacity, thereby increasing
sodium and water retention. This in turn creates a
response by elevating BP. Results from the
hypertensive mice showed significant decreases in both
GFR and urinary sodium velocity when compared to
control. SBP remained elevated in the experimental
group all the while remaining unchanged in the control
group post experiment. This proves that intrarenal AT
II-dependent sodium retention maintains hypertensive
states (16).
Another AT II-dependent experiment was
conducted by Prieto-Carrasquero et al. in 2008 lasting
four weeks. They hypothesized that an increase in
collecting duct (intrarenal) renin within 2-kidney, 1-
clip (2K1C) Goldblatt rats persists regardless of classic
RAS suppression. Age-matched rats with similar initial
BP levels were separated into control (non-
hypertensive) and experimental groups. The
experimental (2K1C) rats were chronically infused
with AT II, had their left renal arteries clipped while
the right renal arteries remained non-clipped, allowing
negative feedback response from classic RAS. Results
showed that both kidneys (clipped and non-clipped) of
the experimental group expressed similar increases in
renin concentration compared to the control group,
which exhibited low intrarenal renin content. Overtime,
the 2K1C rats developed and sustained hypertension,
despite JGA suppression. Thus, AT II-infused
upregulation of intrarenal renin causes cascading
events that prevent high BP to be normalized (13, 14).
A human study performed by Kobori et al. in
2008 involved collection of data from hypertensive
patients and comparing them to age-matched non-
hypertensive participants. 106 individuals were divided
into three groups: normotensive, hypertensive and
hypertensive treated with RAS blocker. Data was
organized into patient profiles. One of the measures
included urinary concentration of AGT (renin-
substrate), which is a biomarker of intrarenal RAS
status. Comparison charts revealed a significant
increase in urinary AGT content amongst the
hypertensive group compared to the control and
treatment groups. Both, the control and treatment
groups displayed similar concentrations. This increase
suggests that high expressions of intrarenal AGT led to
substantial spillover into the filtered fluid and
eventually urine. Since hypertensive patients show a
significant urine angiotensinogen content, it acts as a
novel biomarker of intrarenal RAS status (3).
Although circulating RAS has an active role in
regulating blood pressures to normal, one cannot
ignore the heavy contribution of inappropriately
activated intrarenal RAS in the progression of systemic
hypertension. To combat hypertension, therapeutic
drugs such as ACE inhibitors, ARBs and renin blockers
are used as current treatments (1, 2, 4, 10, 11, 12).
These act on various sites of the classic renin-
angiotensin system to block the downstream effects of
elevating BP levels. However, further research is
required to examine the degree of influence these RAS
inhibitors have on the intrarenal system, specifically
(2). Perhaps, when this is known, science will be able
to identify the hidden cause of essential hypertension,
which is currently of idiopathic nature.
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4. KIN 470 Point: Counterpoint Shraddha Shah
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