How do Na-K-2Cl cotransporters (NKCC) in the loop of Henle drive magnesium (Mg) and calcium (Ca) reabsorption?

From the Guidelines

NKCC in the loop of Henle drives Mg and Ca reabsorption indirectly by creating a positive electrical potential in the lumen and a concentration gradient that enhances paracellular transport of these ions. The primary site for magnesium and calcium reabsorption is the thick ascending limb of the loop of Henle, where approximately 65-70% of filtered magnesium and 20-25% of filtered calcium is reabsorbed 1. NKCC transporters, specifically NKCC2, located on the apical membrane of thick ascending limb cells, actively transport sodium, potassium, and chloride ions from the tubular lumen into the cell. This process is crucial for the reabsorption of magnesium and calcium, as it creates the conditions necessary for their passive reabsorption.

Key Mechanisms

• The positive electrical potential in the lumen relative to the interstitium serves as the driving force for paracellular reabsorption of positively charged ions, including magnesium and calcium, through tight junctions between cells.
• The NKCC-mediated reabsorption of sodium chloride without water creates a concentration gradient that further enhances paracellular transport.
• The tight junctions in this segment contain claudin proteins (particularly claudin-16 and claudin-19) that regulate the permeability to divalent cations, further influencing the reabsorption process, as shown in the pathophysiology of Bartter syndrome 1.

Clinical Implications

• Loop diuretics like furosemide, which inhibit NKCC transporters, can cause increased urinary excretion of magnesium and calcium, potentially leading to deficiencies with chronic use.
• Understanding the role of NKCC in magnesium and calcium reabsorption is essential for managing conditions like Bartter syndrome and for minimizing the risk of electrolyte imbalances in patients treated with loop diuretics 1.

From the Research

NKCC and Ion Reabsorption in the Loop of Henle

• The Na-K-2Cl cotransporter (NKCC2) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL) 2.
• NKCC2 facilitates the reabsorption of NaCl in the TAL, and its transport activity is crucial for the renal reabsorptive capacity for NaCl 2.
• The reabsorption of NaCl in the TAL is indirectly related to the reabsorption of Mg and Ca, as the reabsorption of these ions is influenced by the overall salt and water homoeostasis in the kidney 3, 4.

Mechanism of Mg and Ca Reabsorption

• The association between sodium and calcium reabsorption in the loop of Henle predicts hypercalciuria in patients with a defect in salt reabsorption in this segment, as in Bartter's syndrome 3.
• In contrast, Gitelman's syndrome, which is caused by a transport defect in the distal tube, is characterized by hypocalciuria, suggesting that the reabsorption of Ca is influenced by the transport mechanisms in the distal nephron 3, 4.
• The reabsorption of Mg is also influenced by the transport mechanisms in the loop of Henle and the distal nephron, and hypomagnesemia is a characteristic feature of Gitelman's syndrome 3, 4.

Role of NKCC2 in Mg and Ca Reabsorption

• NKCC2 is not directly involved in the reabsorption of Mg and Ca, but its transport activity influences the overall salt and water homoeostasis in the kidney, which in turn affects the reabsorption of these ions 2, 5.
• The different isoforms of NKCC2, which are expressed in the TAL, may have distinct roles in the reabsorption of NaCl and the regulation of Mg and Ca reabsorption 5.
• The functional significance of NKCC2 isoforms for TAL salt retrieval and for the specific salt sensor function of macula densa cells is still not fully understood, but it is likely that they play a crucial role in the regulation of Mg and Ca reabsorption 5, 6.