Renal water transport in health and disease

Abstract

Saving body water by optimal reabsorption of water filtered by the kidney leading to excretion of urine with concentrations of solutes largely above that of plasma allowed vertebrate species to leave the aquatic environment to live on solid ground. Filtered water is reabsorbed for 70% and 20% by proximal tubules and thin descending limbs of Henle, respectively. These two nephron segments express the water channel aquaporin-1 located along both apical and basolateral membranes. In the proximal tubule, the paracellular pathway accounts for at least 30% of water reabsorption, and the tight-junction core protein claudin-2 plays a key role in this permeability. The ascending limb of Henle and the distal convoluted tubule are impermeant to water and are responsible for urine dilution. The water balance is adjusted along the collecting system, i.e. connecting tubule and the collecting duct, under the control of arginine-vasopressin (AVP). AVP is synthesized by the hypothalamus and released in response to an increase in extracellular osmolality or stimulation of baroreceptors by decreased blood pressure. In response to AVP, aquaporin-2 water channels stored in subapical intracellular vesicles are translocated to the apical plasma membrane and raise the water permeability of the collecting system. The basolateral step of water reabsorption is mediated by aquaporin-3 and -4, which are constitutively expressed. Drugs targeting water transport include classical diuretics, which primarily inhibit sodium transport; the new class of SGLT2 inhibitors, which promotes osmotic diuresis and the non-peptidic antagonists of the V2 receptor, which are pure aquaretic drugs. Disturbed water balance includes diabetes insipidus and hyponatremias. Diabetes insipidus is characterized by polyuria and polydipsia. It is either related to a deficit in AVP secretion called central diabetes insipidus that can be treated by AVP analogs or to a peripheral defect in AVP response called nephrogenic diabetes insipidus. Diabetes insipidus can be either of genetic origin or acquired. Hyponatremia is a common disorder most often related to free water excess relying on overstimulated or inappropriate AVP secretion. The assessment of blood volume is key for the diagnosis and treatment of hyponatremia, which can be classified as hypo-, eu-, or hypervolemic.

Keywords: Aquaporin; Diabetes insipidus; Hyponatremia; Kidney tubule; Water balance.

Fig. 1

Hormonal control of water transport by collecting duct. Arginine vasopressin (AVP) is synthesized in the hypothalamus and released by the posterior pituitary gland. In the renal collecting duct principal cells, AVP binds to the vasopressin receptor type 2 (V2R), which leads to the activation of the protein kinase A (PKA) and increases aquaporin-2 (AQP2) abundance in the apical plasma membrane by stimulating its translocation from intracellular storage vesicles. Water is reabsorbed via AQP2 at the apical membrane and then exits the cell through aquaporin-3 (AQP3) and aquaporin-4 (AQP4) at the basolateral membrane

Fig. 2

Aquaporin (AQP) distribution along the nephron. AQP1 is located in both the apical and basolateral membrane of proximal tubule cells, which is highly permeable to water and accounts for 70% of total water reabsorption. AQP7 is additionally found along the brush border of proximal tubule cells. The thin descending limb of Henle accounts for 20% of water reabsorption via the AQP1 located at both apical and basolateral sides of the plasma membrane. The collecting duct is less permeable to water (0 to 9%) and expresses three aquaporins in principal cells: AQP2 at the apical membrane, and AQP3 and AQP4 at the basolateral membrane

Fig. 3

Major biological and clinical characteristics of the various types of hyponatremias