The discovery of aquaporin-1 (AQP1) answered the long-standing biophysical question of how water specifically crosses biological membranes. In the kidney, at least seven aquaporins are expressed at distinct sites. AQP1 is extremely abundant in the proximal tubule and descending thin limb and is essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel. AQP3 and AQP4 are both present in the basolateral plasma membrane of collecting duct principal cells and represent exit pathways for water reabsorbed apically via AQP2. Studies in patients and transgenic mice have demonstrated that both AQP2 and AQP3 are essential for urinary concentration. Three additional aquaporins are present in the kidney. AQP6 is present in intracellular vesicles in collecting duct intercalated cells, and AQP8 is present intracellularly at low abundance in proximal tubules and collecting duct principal cells, but the physiological function of these two channels remains undefined. AQP7 is abundant in the brush border of proximal tubule cells and is likely to be involved in proximal tubule water reabsorption. Body water balance is tightly regulated by vasopressin, and multiple studies now have underscored the essential roles of AQP2 in this. Vasopressin regulates acutely the water permeability of the kidney collecting duct by trafficking of AQP2 from intracellular vesicles to the apical plasma membrane. The long-term adaptational changes in body water balance are controlled in part by regulated changes in AQP2 and AQP3 expression levels. Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting are seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure. In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy, and syndrome of inappropriate antidiuretic hormone secretion, both AQP2 expression levels and apical plasma membrane targetting are increased, suggesting a role for AQP2 in the development of water retention. Continued analysis of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders.

Aquaporins in the Kidney: From Molecules to Medicine

Water excretion by the kidney is regulated by the peptide hormone vasopressin. Vasopressin increases the water permeability of the renal collecting duct cells, allowing more water to be reabsorbed from collecting duct urine to blood. Despite long-standing interest in this process, the mechanism of the water permeability increase has remained undetermined. Recently, a molecular water channel (AQP-CD) has been cloned whose expression appears to be limited to the collecting duct. Previously, we immunolocalized this water channel to the apical plasma membrane (APM) and to intracellular vesicles (IVs) of collecting duct cells. Here, we test the hypothesis that vasopressin increases cellular water permeability by inducing exocytosis of AQP-CD-laden vesicles, transferring water channels from IVs to APM. Rat collecting ducts were perfused in vitro to determine water permeability and subcellular distribution of AQP-CD in the same tubules. The collecting ducts were fixed for immunoelectron microscopy before, during, and after exposure to vasopressin. Vasopressin exposure induced increases in water permeability and the absolute labeling density of AQP-CD in the APM. In parallel, the APM:IV labeling ratio increased. Furthermore, in response to vasopressin withdrawal, AQP-CD labeling density in the APM and the APM:IV labeling ratio decreased in parallel to a measured decrease in osmotic water permeability. We conclude that vasopressin increases the water permeability of collecting duct cells by inducing a reversible translocation of AQP-CD water channels from IVs to the APM.

https://www.pnas.org/content/pnas/92/4/1013.full.pdf

Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane

Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins — the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines.

/pdf/from-structure-to-disease-the-evolving-tale-of-aquaporin-162r5vifxy.pdf

From structure to disease: the evolving tale of aquaporin biology

The high water permeability characteristic of mammalian red cell membranes is now known to be caused by the protein AQP1 This channel freely permits movement of water across the cell membrane, but it is not permeated by other small, uncharged molecules or charged solutes AQP1 is a tetramer with each subunit containing an aqueous pore likened to an hourglass formed by obversely arranged tandem repeats Cryoelectron microscopy of reconstituted AQP1 membrane crystals has revealed the three-dimensional structure at 3-6 A AQP1 is distributed in apical and basolateral membranes of renal proximal tubules and descending thin limbs as well as capillary endothelia Ten mammalian aquaporins have been identified in water-permeable tissues and fall into two groupings Orthodox aquaporins are water-selective and include AQP2, a vasopressin-regulated water channel in renal collecting duct, in addition to AQP0, AQP4, and AQP5 Multifunctional aquaglyceroporins AQP3, AQP7, and AQP9 are permeated by water, glycerol, and some other solutes Aquaporins are being defined in numerous other species including amphibia, insects, plants, and microbials Members of the aquaporin family are implicated in numerous physiological processes as well as the pathophysiology of a wide range of clinical disorders

Cellular and molecular biology of the aquaporin water channels.

The potent mineralocorticoid aldosterone has a multifaceted role in the pathogenesis of congestive heart failure. In addition to its contribution to salt and water retention, it also promotes organ fibrosis. Although angiotensin-converting–enzyme inhibitors have important therapeutic benefit in heart failure, they do not eliminate the effects of aldosterone. Thus, recent studies have underscored the value of aldosterone-receptor antagonists, such as spironolactone, in the treatment of chronic heart failure. This review article gives an in-depth update on the mechanisms of action of aldosterone and their implications for therapy.

Aldosterone in congestive heart failure

It is now well established that the action of antidiuretic hormone (ADH) is mediated by cAMP and that ADH induces physiological changes in the luminal cell Less certain at this stage are the events that link an elevation of intracellular cAMP to an increase in luminal membrane permeability to water and solutes. In recent years, three observations on the toad bladder have provided important insights into these post-CAMP events: (1) The demonstration that by a variety of maneuvers the changes in water permeability can be dissociated from changes in solute Permeability and therefore that separate pathways are involved.5-7 (2) The observations demonstrating that microtubules and microfilaments are involved in the water permeability response.8-10 (3 ) The finding that intramembrane particle aggregates visualized by freeze-fracture electron microscopy are associated with the modulation of luminal-membrane water pem1eabi1ity.ll-l~ Observations reported by many laboratories clearly demonstrate that these organized membrane structures perform an important role in the action of ADH.ll-la Most workers in the field now strongly suspect that these structures are the site of transmembrane water channels. The evidence that aggregates play a role in the ADH response has been discussed in several review papers.l73 Here we will describe how freeze-fracture observations have led to a new proposal for the mechanism of action of ADH and discuss to what extent this proposal is supported by the available evidence.

ADH Action: Evidence for a Membrane Shuttle Mechanism

Structural and functional study of the rat distal nephron: Effects of potassium adaptation and depletion

Morphologic alterations in the rat medullary collecting duct following potassium depletion

Examination of the toad urinary bladder by freeze-fracture electron microscopy reveals that the mitochondria-rich cells of the epithelium possess distinctive and characteristic membrane structural specialization. Unique rod-shaped intramembrane particles are found in luminal and basal membranes as well as certain intracellular vesicles of this cell type. The consistent finding of two discrete patterns of luminal membrane structural organization supports the possibility that two morphological forms of mitochondria-rich cell exist within the toad bladder epithelium.

James B. Wade

Papers

ADH Action: Evidence for a Membrane Shuttle Mechanism

Structural and functional study of the rat distal nephron: Effects of potassium adaptation and depletion

Morphologic alterations in the rat medullary collecting duct following potassium depletion

Membrane structural specialization of the toad urinary bladder revealed by the freeze-fracture technique. II. The mitochondria-rich cell.

Structural adaptation in initial collecting tubule following reduction in renal mass