Stimuli
Response
Osmotic
Increase in plasma osmolality
↑
Decrease in plasma osmolality
↓
Nonosmotic
Decrease in volume or blood pressure
↑
Increase in volume or blood pressure
↓
Nausea
↑
Pain
↑
Physical stress
↑
Hypoglycemia
↑
Low PO2 and high PCO2
↑
α-adrenergic agents
↓
Β-adrenergic agents
↑
Cholinergic and dopaminergic agents
↑
Angiotensin II
↑
Narcotics
↑
Antimetabolites
↑
Oral hypoglycemics (chlorpropamide)
↑
Ethanol
↓
Phenytoin
↓
Prostaglandins (PGE2)
↓
Atrial natriuretic peptide
↓
Distribution of Aquaporins in the Kidney
Before we discuss the mechanism of action of ADH, it is essential to understand the distribution of water channels (called aquaporins) because of their involvement in water transport across the epithelia. AQPs are membrane water channels that are responsible for water transport in the nephron and other organs. There are 13 AQPs. In the kidney, AQPs 1–4 are involved in water transport. AQP-1 is expressed in the proximal tubule and the descending limb of Henle’s loop at both the apical and basolateral membranes. It is also present in the descending vasa recta. AQP-1 is absent in the thin and thick ascending limbs of Henle’s loop where the water permeability is low. AQP-2 is present in the apical membrane of the principal cells of the cortical, outer medullary, and inner medullary collecting duct, and in the cells of the inner medullary collecting duct. AQP-3 is expressed predominantly in the basolateral membrane of the principal cells of the collecting duct from cortex to the tip of the papilla, whereas AQP-4 is present in the basolateral membrane of the principal cells of the inner medullary collecting duct. Of the four AQPs, only AQP-2 is regulated by ADH. This hormone stimulates the synthesis and insertion of AQP-2 into the apical membrane of the principal cell to promote water permeability .
Mechanism and Actions of ADH
Mechanism
The main actions of ADH are on the kidney. However, as the name vasopressin implies, ADH has pressor effects on the blood vessels. ADH exerts its effects through membrane receptors. To date, four different ADH receptors have been identified. Vasopressin V1 receptors are present on the vascular smooth muscle, liver, and glomerular mesangial cells. Binding of ADH to these receptors increases the concentration of cytosolic Ca2+ through the inositol triphosphate pathway. Vasopressin V2 receptors are present on the epithelial cells of the medullary thick ascending limb and the collecting duct. Vasopressin V3 receptors are present in the kidney, pituitary, heart, and spleen in rats, whereas in humans they are restricted to the pituitary. The Vasopressin V4 receptor (called vasopressin-activated calcium mobilizing receptor) is present in the kidney, heart, brain, and skeletal muscle .
The Vasopressin V2 receptor is the major receptor responsible for water reabsorption in the collecting duct. Briefly, the binding of ADH to this V2 receptor in the collecting duct promotes water reabsorption from the tubular lumen by the following mechanism (Fig. 11.1). ADH binds to the V2 receptor located in the basolateral membrane. The V2 receptor is coupled with a stimulatory G protein. Activation of G protein stimulates adenylate cyclase, which converts ATP (adenosine triphosphate) into cAMP (cyclic adenosine monophosphate). This cAMP activates protein kinase A, which in turn stimulates intracellular vesicles-containing AQP-2 water channels. These AQP-2 water channels are subsequently translocated to the apical membrane by exocytosis of intracellular vesicles for transport of water. This process of translocation is called shuttle hypothesis. Once ADH levels are low, water permeability is decreased with a shift of AQP-2 water channels back into the intracellular vesicles. Water exit at the basolateral membrane is facilitated by AQP-3 and AQP-4 water channels (Fig. 11.1) .
Fig. 11.1
Simplified mechanism of action of ADH on the epithelial cell of the collecting duct. R Vasopressin V2 receptor, AC adenylate cyclase, Gs stimulatory G protein, AQP-2, -3 and – 4 aquaporin-2, -3 and -4 water channels
Actions
ADH has the following actions in the kidney:
1.
In principal cells, it increases water permeability in the cortical and medullary collecting ducts, and plays an important role in urinary concentration and dilution.
2.
It increases the urea transport in the terminal inner medullary collecting duct, and thus participates in urea recycling in the process of urinary concentration.
3.
It activates Na/K/Cl cotransporter and increases NaCl reabsorption in the medullary thick limb of Henle’s loop.
4.
It stimulates NaCl transport and Na transport via ENaC in the cortical collecting duct .
Urinary Concentration and Dilution
The processes that maintain urinary concentration and dilution are briefly summarized as follows:
1.
The kidneys prevent life-threatening deviations in body fluid volume and osmolality by regulating water excretion. During periods of water deprivation, the kidneys reabsorb water and excrete a concentrated (hypertonic) urine with an osmolality of 1,200 mOsm/kg H2O. When water intake is excessive, the kidneys generate a dilute (hypotonic) urine with an osmolality of 50 mOsm/kg H2O. Thus, the kidney can concentrate or dilute urine depending on water availability.
2.
Urine is concentrated because of the combined function of the loop of Henle, which progressively generates a high osmolality (hypertonicity) in the medulla by a process called countercurrent multiplication and the action of ADH on the collecting duct to augment water permeability by regulating AQP-2 water channel. Also, NaCl reabsorption in the thick ascending limb of Henle’s loop is essential to maintain medullary hypertonicity .
3.
The medullary hypertonicity created by countercurrent multiplication is maintained by the vasa recta, the blood vessels that supply the medulla, by a process called countercurrent exchange. Urea, which constitutes about 50 % of the solute in the medullary interstitium, also plays an important role in the maintenance of hypertonicity by a process of urea recycling. ADH plays an important role in urea recycling .
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