Mammalian Distal Tubule: Physiology, Pathophysiology, and Molecular Anatomy

Abstract

The distal tubule of the mammalian kidney, defined as the region between the macula densa and the collecting duct, is morphologically and functionally heterogeneous. This heterogeneity has stymied attempts to define functional properties of individual cell types and has led to controversy concerning mechanisms and regulation of ion transport. Recently, molecular techniques have been used to identify and localize ion transport pathways along the distal tubule and to identify human diseases that result from abnormal distal tubule function. Results of these studies have clarified the roles of individual distal cell types. They suggest that the basic molecular architecture of the distal nephron is surprisingly similar in mammalian species investigated to date. The results have also reemphasized the role played by the distal tubule in regulating urinary potassium excretion. They have clarified how both peptide and steroid hormones, including aldosterone and estrogen, regulate ion transport by distal convoluted tubule cells. Furthermore, they highlight the central role that the distal tubule plays in systemic calcium homeostasis. Disorders of distal nephron function, such as Gitelman's syndrome, nephrolithiasis, and adaptation to diuretic drug administration, emphasize the importance of this relatively short nephron segment to human physiology. This review integrates molecular and functional results to provide a contemporary picture of distal tubule function in mammals.

The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion

“…In the CS, the expression and the activity of the Na + -K + -ATPase is regulated via aldosterone and the MR [30]. In the DCT, the role of aldosterone and the MR for the Na + -K + -ATPase is less clear [19,26]. Therefore, we next investigated the expression of the Na + -K + -ATPase in MR wt and MR ko cells.…”

Ion uptake and acid secretion in zebrafish (Danio rerio)

“…The NCC, a thiazide-sensitive membrane protein, is specifically expressed in the apical membranes of mammalian distal convoluted tubules (DCTs), which are responsible for the reabsorption of 5% to 10% of the total filtered Na + /Cl -reabsorbed by the kidneys (Reilly and Ellison, 2000). Recent studies have opened a new window for elucidating the role of NCC orthologues in Na + /Cl --uptake mechanisms in fish skin/gills.…”

“…Na + concentrations ranging from 35 to 77 mmol l -1 in the lumen of mammalian DCTs (Good et al, 1984) and low intracellular Na + resulting from basolateral NKA provide a sufficient Na + gradient to drive the operation of the apical NCC in DCT cells (Reilly and Ellison, 2000). In contrast, in ambient FW (local tap water in Taipei), zebrafish normally have much lower Na + /Cl -levels, creating ion gradients that may not be favourable for the operation of NCC in apical membranes of NCC cells in zebrafish.…”

Molecular Mechanisms of Primary Hypercalciuria

“…In the distal tubule, calbindin D 28k acts as the principal calcium shuttle (47,118). Calbindin D 9k and parvalbumin, another calcium-binding protein, are found only at the basolateral membrane and may play a role in the extrusion of calcium from the basolateral surface of the cell (125).…”