LAUSR

Objective: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibiton on lowering blood pressure are well characterized in diabetic animals and humans. However, it is unclear whether SGLT2 inhibitors may have antihypertensive effects in non-diabetic kidney disease. This study was undertaken to investigate whether the hypertension in non-diabetic proteinuric kidney disease may be controlled by empagliflozin. Design and method: Male Sprague-Dawley rats were randomly divided into uni-nephrectomized controls (NX, n = 5), uni-nephrectomy plus doxorubicin-treated rats (NXD, n = 5), and uni-nephrectomy plus doxorubicin/empagliflozin-cotreated rats (NXDE, n = 5). Doxorubicin was administered via femoral vein in a single bolus (5 mg/kg) after 7 days of right nephrectomy. Empagliflozin (20 mg/kg/d) was daily given in food slurry. After 5 weeks of empagliflozin administration, kidneys were harvested for immunoblotting of sodium transporters. Results: At baseline (Day 0, immediately before doxorubicin treatment), systolic blood pressures were not different between group: NX, 120 ± 1; NXD, 120 ± 1; and NXDE, 119 ± 3 mmHg. From Day 7 (NX, 127 ± 1; NXD, 163 ± 3; and NXDE, 155 ± 1 mmHg) through Day 35 (NX, 130 ± 1; NXD, 172 ± 1; and NXDE, 160 ± 1 mmHg), remarkable hypertension was induced by doxorubicin and significantly relieved by empagliflozin cotreatment (P < 0.01). Significant proteinuria was produced from Day 14 and increased thereafter by doxorubicin but not decreased by empagliflozin cotreatment. Osmotic diuresis was evidently induced by empagliflozin administration from Day 7 (NXDE 40.7 ± 1.3 vs. NXD 21.7 ± 1.1 mosmoles/d, P < 0.01) through Day 35 (NXDE 52.3 ± 4.0 vs. NXD 27.9 ± 1.7 mosmoles/d, P < 0.01), in parallel with natriuresis and glycosuria. Immunoblot analysis from the kidney showed that compared with NXD, NXDE had decreased protein abundance of Na-K-2Cl cotransporter-2 (100 ± 31 vs. 40 ± 8%, P < 0.05) and Na-K-ATPase alpha1 subunit (100 ± 13 vs. 51 ± 13%, P < 0.05) but no change in Na/H exchanger-3. Conclusions: In our uni-nephrectomized rat model, doxorubicin-induced hypertension was significantly ameliorated by empagliflozin administration. This antihypertensive effect was associated with decreased expression of renal sodium transporters and resultant increased natriuresis, but not with proteinuria reduction.