Chronic Furosemide Administration Alters Abundance of Sodium Transporters in Rat Kidney

Yoon-Kyu OH; Ki-Young NA; Jay-Wook LEE; Hye-Ryun CHANG; Young-Sun PARK; Junghwan PARK; Kwon-Wook JOO; Gheun-Ho KIM; Jung-Sang LEE; Jin-Suk HAN

BACKGROUND:

Furosemide inhibit NaCl absorption in the thick ascending limb and produce an increase in distal delivery of Na+. We carried out semiquantitative immunoblotting and immunohistochemistry of rat kidneys to investigate whether chronic furosemide infusion is associated with compensatory increases in the abundance of Na+ transporters in distal nephron.

METHODS:

Osmotic minipumps were implanted into Sprague-Dawley rats to deliver 12 mg/day of furosemide(n=6) with simultaneous administration of 0.8% NaCl and 0.1% KCl in drinking water for 7 days.

RESULTS:

Compared with vehicle infused controls, urine volume and urine sodium amount were increased. However, there were no differences in body weight, serum aldosterone, and creatinine clearance. The abundance of Na+-K+-2Cl- cotransporter after furosemide infusion was increased in cortex (151+/-10 vs. 100+/-10%, p< 0.05) and outer medulla (122+/-5 vs. 100+/-3%, p< 0.01). In furosemide infusion group, the abundance of all three subunits of epithelial sodium channel (ENaC) was increased both in cortex (alpha 187+/-25 vs. 100+/-17%, p< 0.05; beta 155+/-8 vs. 100+/-15%, p< 0.05; gamma 168+/-16 vs. 100+/-9%, p< 0.05) and outer medulla (alpha 171+/-27 vs. 100+/-17%, p< 0.05; beta 986+/-91 vs. 100+/-33%, p< 0.01; gamma 242+/-24 vs. 100+/-22%, p< 0.01). Consistent with these results, ENaC beta-subuint immunohistochemistry showed a remarkable increase in immunoreactivity in the principal cells of collecting ducts with furosemide treatment.

CONCLUSION:

These increases in the abundance of ENaC protein may account for the generation of diuretic tolerance.

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