Long-Term Adaptation of Renal Ion Transporters to Chronic Diuretic Treatment

Abstract

Loop and thiazide diuretics are clinically useful to induce negative sodium balance. However, with chronic treatment, their effects tend to be blunted since the kidney adapts to diuretics. Molecular identification of the renal ion transporters has provided us with a new understanding of the mechanisms of intrarenal adaptation to diuretics at molecular levels. In the kidney, loop and thiazide diuretics are secreted from the proximal tubule via the organic anion transporter-1 (OAT1) and exert their diuretic action by binding to the Na-K-2Cl cotransporter type 2 (NKCC2) in the thick ascending limb and the Na-Cl cotransporter (NCC) in the distal convoluted tubule, respectively. Recent studies in animal models suggest that abundance of these ion transporters is affected by long-term diuretic administration. Downstream from the primary site of diuretic action, an increase in epithelial Na⁺ channel (ENaC) abundance is induced by chronic furosemide or hydrochlorothiazide treatment. This adaptation is consistent with previous reports showing cellular hypertrophy and increased Na⁺ absorption in distal tubular segments. The abundance of NKCC2 and NCC is increased by furosemide and hydrochlorothiazide, respectively. This compensatory upregulation suggests that either diuretic may activate the ion transporter within the primary site of action. In the proximal tubule, the abundance of OAT1 is increased by chronic treatment with furosemide or hydrochlorothiazide. This upregulation of OAT1 seems to be induced by substrate stimulation, lessening diuretic tolerance associated with long-term diuretic use.

Efficacy and Safety of Ultrafiltration in Decompensated Heart Failure Patients With Renal Insufficiency

“…Diuretics are the first-line drugs for decompensated heart failure, but patients with decompensated heart failure complicated by renal insufficiency are more vulnerable to suffer diuretic resistance [26][27][28][29] and have even poorer outcomes. 30) Moreover, prolonged diuretic use is sometimes linked with increased mortality and mobility in congestive heart failure patients due to electrolyte abnormalities, neurohormonal activation, renal dysfunction, and diuretic resistance.…”

Everything we always wanted to know about furosemide but were afraid to ask

“…Indeed, long-term use of furosemide can increase the abundance of NKCC2 in the thick ascending limb and OAT1 in the proximal tubule (84). Furthermore, furosemide infusion increases the abundance of all three subunits of the epithelial Na ϩ channel in connecting tubules, cortical collecting ducts, outer medullary collecting ducts, and inner medullary collecting ducts (108).…”

“…QUESTIONS ABOUT FUROSEMIDE diuresis (84). According to Kaissling and Stanton (78), furosemide-induced increases in distal Na ϩ concentration is a stimulus for epithelial cell growth in distal tubules in animal models.…”

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms

“…However, compensatory mechanisms appear to accommodate increased distal delivery under most circumstances. A common example is the compensatory response to the chronic administration of loop diuretics, which not only increase distal delivery but also block TGF (43,89). After an initial loss of volume, proximal and distal compensatory adaptations achieve a new steady-state within three to four days, despite continued use of the diuretic (43,89).…”

“…A common example is the compensatory response to the chronic administration of loop diuretics, which not only increase distal delivery but also block TGF (43,89). After an initial loss of volume, proximal and distal compensatory adaptations achieve a new steady-state within three to four days, despite continued use of the diuretic (43,89). A similar time course is observed in response to large perturbations in salt intake, demonstrating that, in addition to the rapid TGF response, chronic adaptations effectively regulate volume.…”