Discuss the Role of ANP and the Renin-aldosterone axis in controlling volume and
hence pressure chronically.
The extracellular fluid volume (ECFV) is an important parameter in blood pressure (BP)
homeostasis. Long-term BP control relies largely on regulation of ECFV by the kidneys
through four parallel feedback pathways, they are either neural or hormonal and are
elicited by ECFV changes sensed by baroreceptors. In this essay, we focus on how the
hormonal pathways, namely the atrial natriuretic peptide (ANP) pathway and the
renin-aldosterone axis, are involved in controlling ECFV, thereby impacting on chronic
pressure control.
To begin with, regulation of ECFV is achieved by adjusting the NaCl content in the body
and is important in maintaining BP, ensuring a stable tissue perfusion and function.
During BP changes, the kidneys play a primary role in bringing it back to the set point
through modulating the urinary excretion of sodium called natriuresis. Sodium
movement is followed by water flux so natriuresis is the key modulator of ECFV hence
BP, the pressure natriuresis response (PN) describes how disturbances to BP can be
restored by the kidneys, which we will go into further details later. The two hormonal
pathways that describe how the kidneys control ECFV, as mentioned earlier, are the
ANP pathway and renin-aldosterone axis. ANP is a peptide hormone that increases
sodium excretion, while hormones produced in the renin-aldosterone decrease sodium
excretion by enhancing its retention. The regulation of these pathways leads to a single
effector function to modify sodium hence water excretion, so ECFV is kept constant.
The hormonal renin-angiotensin-aldosterone axis is the first effector pathway, it plays
a crucial role in pressure-volume homeostasis of the kidneys by promoting sodium
retention, the pathway is therefore stimulated by low ECFV and suppressed in ECFV
expansion. The role of kidneys in the axis is the secretion of renin, which activates the
pathway by cleaving angiotensinogen into angiotensin I. Renin and its precursor
prorenin are synthesized and stored within granular cells of the juxtaglomerular
apparatus, they are specialized smooth muscle found mainly in the afferent arteriole
which can switch between a contractile and renin-secreting phenotype according to
external stimuli. Juxtaglomerular cells are sensitive to effective circulating volume
(ECV) that refers to the volume of arterial blood perfusing tissues, which is usually
reflective of ECFV unless uncoupled in diseases. To illustrate, a decrease in ECV is
sensed and lead to stimulation of renin release in three ways: (1) sympathetic nerve
stimulation of the juxtaglomerular apparatus is enhanced when high pressure
baroreceptors in the carotid sinus and aortic arch sense a lowered ECV, leading to a
raised renin release. This is supported by findings from Seifarath et al. (2002) when the
group showed a significant suppression of renin in hypertension patients receiving
, beta blocker therapy. (2) juxtaglomerular granular cells in the afferent arteriole act as
baroreceptors to sense renal perfusion pressure, smaller stretch due to low ECV
decreases intracellular calcium concentration which in turn increases renin secretion.
Here, a calcium paradox is demonstrated where calcium inhibits release, instead of
stimulating release in most secretory processes. (3) the macula densa detects low
sodium chloride concentrations in the distal tubule associated with low ECV and
stimulates renin release. Through these sensing and signalling cascades, activation of
the renin-aldosterone axis can be modulated according to changes in ECFV to maintain
it at a relatively constant value of approximately 14L.
The two major enzymes that play a part in sodium hence water retention is
angiotensin II and aldosterone, we will now look at how they are produced when ECFV
is low and their major actions. Upon conversion of angiotensinogen into angiotensin I
by renin from the kidneys, angiotensin-converting enzyme (ACE) rapidly cleaves
angiotensin I into its physiologically active form angiotensin II (ANG II) which has
several important actions that increases ECFV. Haemodynamic actions of ANG II have
an impact on ECFV, for example, vasoconstriction effects of ANG II acts on efferent
arterioles over afferent arterioles which leads to a larger filtration rate hence filtration
fraction. This modifies the balance of Starling’s forces in the peritubular capillaries by
reducing the hydrostatic pressure while raising the colloid osmotic pressure, favouring
sodium and fluid reabsorption. Vasa recta is also constricted by ANG II, reducing the
medullary blood flow so there is less washout of the hypertonicity in the medulla
interstitium, thereby enhancing passive sodium reabsorption along the thin ascending
limb. Furthermore, ANG II affect apical membrane sodium transporter activity to
promote sodium reabsorption along the kidney tubules. ANG II binds to receptors in
proximal tubule cells to stimulate sodium-hydrogen exchanger 3 (NHE3) via protein
kinase C, leading to greater sodium reabsorption in the proximal tubule. Meanwhile,
ANG II upregulates the expression of NHE3 and sodium-potassium-chloride
cotransporter 2 (NKCC2) in the thick ascending limb, as well as enhancing sodium-
chloride cotransporter and epithelial sodium channel (ENaC) activity in the distal
convoluted and collecting tubule respectively. Since water follows sodium fluxes, these
transporters increase ECFV by enhancing sodium reabsorption. Another important
function of ANG II is to stimulate aldosterone release from the adrenal cortex,
aldosterone is the final element in the renin-aldosterone axis and it further promotes
sodium reabsorption by acting on various transporters. As a steroid hormone,
aldosterone binds to cytoplasmic mineralocorticoid receptors that elicits a cascade
that upregulates transcription of several apical transporters and proteins. For example,
the expression of apical ENaC, mainly in the distal convoluted tubule, is upregulated by
aldosterone. The number of some other proteins including basolateral sodium-
potassium pump is increased by aldosterone too. Through the described effector
