Renal aquaporins: Role in water balance disorders

The discovery of aquaporin (AQP) membrane water channels by Peter Agre and co-workers answered a long-standing biophysical question of how water crosses biological membranes and provided insight, at the molecular level, into the fundamental physiology of water balance regulation and the pathophysiology of water balance disorders. In the kidney, AQP1-AQP4, AQP6-AQP8 and AQP11 are expressed and multiple studies have underscored the essential roles of AQP1-AQP4 in renal regulation of body water balance. Vasopressin regulates acutely the water permeability of the kidney collecting duct by regulation of AQP2 trafficking from intracellular vesicles to the apical plasma membrane. This involves complex signalling mechanisms. In addition, long-term regulation of AQP2 and AQP3 expression act in concert with acute regulation of AQP2 to tightly control collecting duct water reabsorption and hence body water balance. Importantly, mutations or dysregulation of renal AQPs is involved in water balance disorders. Mutations in AQP2 lead to nephrogenic diabetes insipidus (NDI). Downregulation of AQP2 expression and/or dysregulation of AQP2 trafficking leads to urinary concentrating defects seen in acute kidney injury, drug-induced polyuria (e.g. lithium-induced NDI), compulsive water drinking (polydipsia) and diseases associated with electrolyte disorders (hypokalemia and hypercalcemia). Conversely, upregulation and enhanced apical trafficking of AQP2 is involved in diseases associated with water retention such as congestive heart failure.