Ganong's Review of Medical Physiology, 23rd Edition

670
SECTION VIII
Renal Physiology

lost from both the intracellular and extracellular fluid com-
partments; but loss of Na

• in the stools (diarrhea), urine
  (severe acidosis, adrenal insufficiency), or sweat (heat pros-
  tration) decreases ECF volume markedly and eventually leads
  to shock. The immediate compensations in shock operate
  principally to maintain intravascular volume, but they also
  affect Na


• 
  

  balance. In adrenal insufficiency, the decline in
  ECF volume is due not only to loss of Na

  
  


• 
  

  in the urine but
  also to its movement into cells. Because of the key position of
  Na

  
  


• 
  

  in volume homeostasis, it is not surprising that more
  than one mechanism has evolved to control the excretion of
  this ion.
  The filtration and reabsorption of Na

  
  


• 
  

  in the kidneys and the
  effects of these processes on Na

  
  


• 
  

  excretion are discussed in
  Chapter 38. When ECF volume is decreased, blood pressure
  falls, glomerular capillary pressure declines, and the glomerular
  filtration rate (GFR) therefore falls, reducing the amount of Na

  
  


• 
  

filtered. Tubular reabsorption of Na

• is increased, in part
  because the secretion of aldosterone is increased. Aldosterone
  secretion is controlled in part by a feedback system in which the
  change that initiates increased secretion is a decline in mean
  intravascular pressure. Other changes in Na


• 
  

  excretion occur
  too rapidly to be due solely to changes in aldosterone secretion.
  For example, rising from the supine to the standing position
  increases aldosterone secretion. However, Na

  
  


• 
  

  excretion is
  decreased within a few minutes, and this rapid change in Na

  
  


• 
  

excretion occurs in adrenalectomized subjects. It is probably
due to hemodynamic changes and possibly to decreased ANP
secretion.
The kidneys produce three hormones: 1,25-dihydroxychole-
calciferol (see Chapter 23), renin, and erythropoietin. Natri-
uretic peptides, substances secreted by the heart and other
tissues, increase excretion of sodium by the kidneys, and an
additional natriuretic hormone inhibits Na, K ATPase.

THE RENIN–ANGIOTENSIN SYSTEM

RENIN

The rise in blood pressure produced by injection of kidney ex-
tracts is due to
renin,
an acid protease secreted by the kidneys
into the bloodstream. This enzyme acts in concert with angio-
tensin-converting enzyme to form angiotensin II (Figure 39–6).
It is a glycoprotein with a molecular weight of 37,326 in hu-
mans. The molecule is made up of two lobes, or domains, be-
tween which the active site of the enzyme is located in a deep
cleft. Two aspartic acid residues, one at position 104 and one at
position 292 (residue numbers from human preprorenin), are
juxtaposed in the cleft and are essential for activity. Thus, renin
is an aspartyl protease.
Like other hormones, renin is synthesized as a large prepro-
hormone. Human
preprorenin
contains 406 amino acid resi-
dues. The
prorenin
that remains after removal of a leader
sequence of 23 amino acid residues from the amino terminal
contains 383 amino acid residues, and after removal of the pro

sequence from the amino terminal of prorenin, active

renin

contains 340 amino acid residues. Prorenin has little if any

biologic activity.

Some prorenin is converted to renin in the kidneys, and

some is secreted. Prorenin is secreted by other organs,

including the ovaries. After nephrectomy, the prorenin level

in the circulation is usually only moderately reduced and

may actually rise, but the active-renin level falls to essen-

tially zero. Thus, very little prorenin is converted to renin in

the circulation, and active renin is a product primarily, if

not exclusively, of the kidneys. Prorenin is secreted consti-

tutively, whereas active renin is formed in the secretory

granules of the juxtaglomerular cells, the cells in the kid-

neys that produce renin (see below). Active renin has a half-

life in the circulation of 80 min or less. Its only known func-

tion is to split the decapeptide

angiotensin I

from the

amino terminal end of

angiotensinogen (renin substrate)

(Figure 39–7).

ANGIOTENSINOGEN

Circulating angiotensinogen is found in the

α

2

-globulin frac-

tion of the plasma (Figure 39–6). It contains about 13% carbo-

hydrate and is made up of 453 amino acid residues. It is

synthesized in the liver with a 32-amino-acid signal sequence

that is removed in the endoplasmic reticulum. Its circulating

level is increased by glucocorticoids, thyroid hormones, estro-

gens, several cytokines, and angiotensin II.

ANGIOTENSIN-CONVERTING

ENZYME & ANGIOTENSIN II

Angiotensin-converting enzyme (ACE)

is a dipeptidyl car-

boxypeptidase that splits off histidyl-leucine from the physio-

logically inactive angiotensin I, forming the octapeptide

angiotensin II

(Figure 39–7). The same enzyme inactivates

bradykinin (Figure 39–6). Increased tissue bradykinin pro-

duced when ACE is inhibited acts on B

2

receptors to produce

the cough that is an annoying side effect in up to 20% of

FIGURE 39–6

Formation and metabolism of circulating

angiotensins.

Angiotensinogen

Angiotensin I

Angiotensin II

AIII, AIV,

others

Various

peptidases

Inactive

metabolites

Renin

Angiotensin-converting enzyme

AT 1 receptors

AT 2 receptors

Bradykinin

Inactive

metabolites