OBJECTIVE 2. TO UNDERSTAND THE MECHANISM OF ACTION OF ADH ON THE KIDNEY.

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A. ADH increases the water permeability of principal cells in the late sections of the distal tubule and in the collecting tubule. ADH specifically binds to V₂ receptors on the basolateral membranes of principal cells. The receptor is coupled via a GTP-requiring stimulatory protein (Gs protein) to the enzyme adenylyl cyclase. The enzyme stimulates the production of cyclic AMP which activates protein kinase A. This kinase induces the insertion (exocytosis) of aggrephores or vesicles containing intramembranous particles into the apical membrane. These particles are the water channels, aquaporin 2. Changes in the cytoskeleton (micro-filaments and microtubules) apparently are associated with the changes induced by ADH and intracellular calcium may also be involved. Aquaporins 3 and 4 form the water channels in the basolateral membrane of the principal cells. These are not regulated by ADH; they are constitutively active.

Fig. 7-3. The mechanism of action of ADH on principal cells. V2 = vasopressin 2 receptor. Gs = stimulatory G protein, AC = adenylyl cyclase, AQ2 = aquaporin 2.

B. ADH is a permissive agent in that it establishes a high permeability but not the force for water movement. The osmotic gradients required to drive that water movement are provided by solute transport mechanisms and by the countercurrent system. ADH stimulates salt transport in the thick ascending limb of some species but apparently not in the human. ADH may also cause constriction of the initial segments of the vasa recta and thereby slow the medullary blood flow rate. This would enhance the effectiveness of the countercurrent system (See below). ADH does not have an effect on GFR or on proximal tubular reabsorption.

C. Changes in circulating levels of ADH can occur within a span of a few minutes and the effect of these changes on collecting tubular water reabsorption also occur quickly (10-20 min). Thus, ADH is involved in short term as well as long term regulation of water reabsorption.

QUESTIONS:  
2. How does the combination of ADH with a receptor on the basolateral surface of principal cells in the collecting tubule result in increased water permeability of the apical membrane?

3. What, in addition to the effect of ADH, is required to increase the rate of water reabsorption by the collecting tubule?

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