title: 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.
authors.affiliation: Department of Internal Medicine and Institute of Biomedical Sciences, Hanyang University College of Medicine, Seoul, Korea. kimgh@hanyang.ac.kr
authors.forename: Gheun-Ho
authors.initials: GH
authors.lastname: Kim
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001581:Benzothiadiazines; D004232:Diuretics; D004361:Drug Tolerance; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D027361:Organic Anion Transporters / Q000502:physiology*; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology*
chemical_list: D001581:Benzothiadiazines; D004232:Diuretics; D027361:Organic Anion Transporters; D049993:Sodium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters