Abstract
The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice.
Highlights
The distal convoluted tubule (DCT) is the portion of the nephron that is immediately downstream of the macula densa
The DCT is the shortest segment of the nephron, spanning only about 5 mm in length in humans [1], it plays a critical role in a variety of homeostatic processes, including sodium chloride reabsorption, potassium secretion, and calcium and magnesium handling
Because the With-No-Lysine [amino acid5K] kinases (WNKs) are the only known activators of Ste20-like prolinealanine rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1) in the kidney, these findings strongly suggest that hormones that regulate BP and extracellular fluid volume status recruit WNK-dependent signaling processes to activate NaCl cotransporter (NCC) through SPAK and OSR1 (Figure 7)
Summary
The distal convoluted tubule (DCT) is the portion of the nephron that is immediately downstream of the macula densa. It was shown that tacrolimus stimulates the activity of NCC, likely by enhancing its phosphorylation through the WNK-SPAK/OSR1 pathway (Figure 7) [67] Consistent with this finding, renal transplant patients on tacrolimus exhibited a greater urinary fractional excretion of chloride on bendroflumethiazide, indicating that tacrolimus-associated hypertension and hyperkalemia may be highly sensitive to thiazide diuretics [67]. A current theory is that the lack of functional Kv1.1 channels decreases the efflux of potassium cations into the lumen, which, in turn, would be expected to make the intracellular voltage on the luminal membrane more positive, decreasing the voltage gradient for luminal Mg21 entry This hypothesis is provocative, the pathophysiology may not be so simple: as discussed above in the section on ROMK gating, such a change in the luminal membrane potential would be expected to markedly enhance ROMK-mediated K1 secretion and cause hypokalemia, which is not observed in the disorder. That our understanding of the regulatory machinery of the DCT is more complete, such investigations can be pursued with the intent of understanding disease pathogenesis and developing new strategies for the treatment of DCT-related disorders, such as hypertensive and/or edematous states, hyper- or hypokalemic tubulopathies, disorders of divalent ion balance, and nephrolithiasis
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