Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

Abstract

The role of ATP-binding cassette transporters in the urinary excretion of diuretics was investigated. Significant ATPdependent uptake of hydrochlorothiazide (HCT) and furosemide was observed in membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and breast cancer resistance protein (BCRP). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of both compounds by MRP4. The functional importance of MRP4 and BCRP in the urinary excretion of HCT and furosemide was investigated using gene knockout mice. The renal clearance of HCT and furosemide was reduced significantly but not abolished in Mrp4 knockout mice compared with wild-type mice (9.0 ؎ 0.9 versus 15 ؎ 2 ml/min per kg for HCT and 1.9 ؎ 0.3 versus 2.7 ؎ 0.1 ml/min per kg for furosemide), and the amount of HCT that was associated with the kidney specimens was greater in Mrp4 knockout mice (21 ؎ 3 versus 13 ؎ 1 nmol/g kidney). In contrast, Bcrp makes only a negligible contribution because the urinary excretion was unchanged in Bcrp knockout mice. Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells.

Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney

“…32 Decreased Met levels with altered DNA methylation may contribute to kidney injury because stimulation of HGF signaling reduces interstitial fibrotic changes in the diabetic kidney. 20 Persistent changes in mRNA levels with altered DNA methylation of Abcc4, which is involved in the urinary excretion of drugs such as furosemide and thiazides, 33 and of Slco1a1, another transporter, potentially induce alterations in drug pharmacokinetics and toxicity.…”

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

“…Thus Oat1 Ϫ/Ϫ and Oat3 Ϫ/Ϫ mice present a very similar rightward shift in the dose-natriuresis curves for both bendroflumethiazide and furosemide (11). Previous studies showed that mice lacking the multidrug resistance-associated protein 4 (MRP4), which localizes to the apical membrane of the proximal tubule, have a reduced renal clearance of furosemide and hydrochlorothiazide, but other transporters maintain a significant efflux into the proximal tubule lumen in these mice without fully compensating for the absence of MRP4 (14). Our studies indicate that both OAT1 and OAT3 contribute to basolateral uptake, and thus renal secretion, of furosemide and thiazide diuretics in vivo and that lack of either one is not fully compensated by the other.…”

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

“…Because thiazide diuretics act in the tubular lumen, their action requires successful delivery to the DCT. This is mediated by active secretion of thiazide diuretics in the proximal tubule through organic anion transporter and multidrug resistance-associated protein 4 [39,114]. This explains why a reduction in glomerular filtration rate results in reduced efficacy of thiazide diuretics.…”