Molecular Physiology of Water Balance

THE HYPOTHALAMIC-NEUROHYPOPHYSEAL-RENAL AXIS NORMALLY MAINtains water balance during variations in water intake and nonrenal losses of water. Failure of this mechanism is common in hospitalized patients, and it results in a variety of water-balance disorders. In this article, we begin by reviewing the classic, integrative principles of water balance in mammals and then use this classic model as a framework to discuss the genes and gene products (proteins) involved in water balance. In so doing, our goal is to provide clinicians with a mechanistic basis for decisions regarding the diagnosis and treatment of water-balance disorders. The regulation of water balance is governed by a high-gain feedback mechanism involving the hypothalamus, the neurohypophysis, and the kidneys (Fig. 1). Osmoreceptors in the hypothalamus, which originally were described by Verney,(1) sense plasma osmolality. The molecular mechanism of osmosensing has recently been described by Danziger and Zeidel.(2) It is, in part, dependent on activation of nonselective calcium-permeable cation channels in osmosensing neurons that can serve as stretch receptors. When plasma osmolality increases to levels above a physiologic threshold (290 to 295 mOsm per kilogram of water in most persons), there is increased secretion of the peptide hormone vasopressin from vasopressinergic nerve endings in the neurohypophysis. High osmolality also triggers thirst. Vasopressin binds to receptors in the kidney that decrease excretion of water (Fig. 2), and a greater fraction of filtered water is returned to the blood. The rate of water excretion can vary over a broad range in response to changes in plasma vasopressin levels without substantial changes in net solute excretion (osmolar clearance). This independent control of water and solute excretion is the result of specialized urinary concentrating and diluting mechanisms; these mechanisms are reviewed elsewhere.(3) Increased renal reabsorption of water in response to vasopressin lowers plasma osmolality, thereby reducing the stimulus for vasopressin secretion and thirst and completing the feedback loop (Fig. 1). Table 1 provides a list of the major proteins that are responsible for components of the integrative model shown in Figure 1. These proteins are the focus of this review.