Developmental changes in renal tubular transport-an overview

Abstract

The adult kidney maintains a constant volume and composition of extracellular fluid despite changes in water and salt intake. The neonate is born with a kidney that has a small fraction of the glomerular filtration rate of the adult and immature tubules that function at a lower capacity than that of the mature animal. Nonetheless, the neonate is also able to maintain a constant extracellular fluid volume and composition. Postnatal renal tubular development was once thought to be due to an increase in the transporter abundance to meet the developmental increase in glomerular filtration rate. However, postnatal renal development of each nephron segment is quite complex. There are isoform changes of several transporters as well as developmental changes in signal transduction that affect the capacity of renal tubules to reabsorb solutes and water. This review will discuss neonatal tubular function with an emphasis on the differences that have been found between the neonate and adult. We will also discuss some of the factors that are responsible for the maturational changes in tubular transport that occur during postnatal renal development.

Keywords: Nephron; Ontogeny of renal transport; Renal development; Sodium transport.

Figure 1

Cartoon of a proximal tubular cell. The top cell is an early proximal tubular cell near the glomerulus depicting the reabsorption of organic solutes and bicarbonate. The lumen is acidified predominantly by an apical Na⁺/H⁺ exchanger. The basolateral Na⁺/K⁺-ATPase lowers intracellular sodium and generates the driving force for this active transport which is by and large sodium dependent. The cell below depicts a late proximal tubular cell where there is a chloride gradient generated by the preferential reabsorption of bicarbonate over chloride ions in the early proximal tubule. Thus, the late tubular fluid is mostly composed of NaCl, which is actively reabsorbed via the apical Na⁺/H⁺ and Cl⁻/Base exchangers. The higher luminal chloride provides a concentration gradient for passive chloride transport along the paracellular pathway. Since the concentration of bicarbonate in the blood is greater than the lumen, bicarbonate could diffuse back into the lumen, but the tight junction is quite impermeable to bicarbonate. In this and all figures, the black circles depict transporters that require ATP.

Figure 2

This figure shows the apical protein expression of the Na⁺/H⁺ exchanger during postnatal development. As shown NHE8 is highly expressed in the neonate while NHE3 is the predominant Na⁺/H⁺ exchanger in the adult proximal tubule. The isoform change occurs at the time of weaning and is likely mediated by the increase in thyroid hormone and glucocorticoids that occur during that time. (Figure reproduced from reference [41], used with permission).

Figure 3

The thick ascending limb reabsorbs 25% of the filtered NaCl. The NKCC on the apical membrane is the transporter that is inhibited by loop diuretics. The recycling of potassium across the apical potassium channel (ROMK), results in a lumen positive potential difference. This positive lumen potential provides a driving force for passive cation absorption along the paracellular pathway. The paracellular pathway in the thick ascending limb is very permeable to cations. A mutation in transporters involved in thick ascending limb transport depicted here can cause Bartter’s syndrome.

Figure 4

The distal convoluted tubule is responsible for 5–10% of NaCl transport. The apical membrane NaCl cotransporter is the one inhibited by thiazide diuretics. Mutations in the NaCl cotransporter result in Gitelman’s syndrome.

Figure 5

This figure depicts the three cell types in the collecting duct. The top cell is the principal cell. Sodium is absorbed across the apical membrane through a channel designated ENaC. The driving force is the basolateral Na⁺/K⁺-ATPase that lowers intracellular sodium. Sodium transport across the apical membrane results in a lumen negative potential difference that is itself the driving force for potassium secretion through a potassium channel designated ROMK. The principal cell also expresses water channels (aquaporin 2) that are inserted into the apical membrane in response to vasopressin to increase water flow across this cell into the hypertonic medulla in order to produce concentrated urine. Below this cell is the type A intercalated cell which plays a role in renal acidification. Both the proton pump and H⁺/K⁺-ATPase are involved in luminal proton secretion. The third cell is a type B intercalated cell, which secretes bicarbonate under conditions of a metabolic alkalosis. Note that the proton pump is on the basolateral membrane of this cell.