Physiological role of SLC12 family members in the kidney

Abstract

The solute carrier family 12, as numbered according to Human Genome Organisation (HUGO) nomenclature, encodes the electroneutral cation-coupled chloride cotransporters that are expressed in many cells and tissues; they play key roles in important physiological events, such as cell volume regulation, modulation of the intracellular chloride concentration, and transepithelial ion transport. Most of these family members are expressed in specific regions of the nephron. The Na-K-2Cl cotransporter NKCC2, which is located in the thick ascending limb, and the Na-Cl cotransporter, which is located in the distal convoluted tubule, play important roles in salt reabsorption and serve as the receptors for loop and thiazide diuretics, respectively (Thiazide diuretics are among the most commonly prescribed drugs in the world.). The activity of these transporters correlates with blood pressure levels; thus, their regulation has been a subject of intense research for more than a decade. The K-Cl cotransporters KCC1, KCC3, and KCC4 are expressed in several nephron segments, and their role in renal physiology is less understood but nevertheless important. Evidence suggests that they are involved in modulating proximal tubule glucose reabsorption, thick ascending limb salt reabsorption and collecting duct proton secretion. In this work, we present an overview of the physiological roles of these transporters in the kidney, with particular emphasis on the knowledge gained in the past few years.

A guide to plasma membrane solute carrier proteins

“…The flux of K + and Cl À ions and the resulting movement of water across the membrane largely regulate changes to cell volume and concurrent cell movement [351]. The SLC12 family contains 9 proteins, which encode for electroneutral cation-chloride cotransporters [352,353]. This family includes two main subfamilies: transporters that are sodium-dependent and those that are sodium-independent [353].…”

“…The SLC12 family contains 9 proteins, which encode for electroneutral cation-chloride cotransporters [352,353]. This family includes two main subfamilies: transporters that are sodium-dependent and those that are sodium-independent [353]. These proteins have a common structure, consisting of 12 TM segments with intracellular N and C termini [352].…”

Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC

“…The mechanism by which uromodulin regulates NCC activation is unclear and will require dedicated in vitro investigations. On the basis of the close homology between the cotransporters, 38 one could hypothesize that mechanisms similar to those reported for NKCC2 could operate. It is currently unclear how uromodulin modulates the activity of NKCC2; previous studies incriminated the SPAK/OSR1 pathway, 15 tumor necrosis factor-a signaling, 14 or modulations of intracellular Cl À levels.…”

Hydrochlorothiazide and acute urinary acidification: The “voltage hypothesis” of ENaC‐dependent H+ secretion refuted

“…Hydrochlorothiazide (HCT) is commonly used as an antihypertensive drug due to its mild diuretic action. HCT inhibits the Na + , Cl − cotransporter (NCC) in the distal convoluted tubule, hereby leading to an increase in diuresis and natriuresis …”