Abstract
The ketone body precursor 1,3-Butanediol (BD) has been reported to lower blood pressure in male Dahl Salt-sensitive rats fed a 2% NaCl diet and female S.SHR(11) rats on a 0.3% NaCl diet. Treatment in female S.SHR(11) was also associated with weight loss and suppression of renal injury. The present study tested whether BD attenuates hypertension and renal injury in male S.SHR(11) rats. The S.SHR(11) rat is a congenic strain generated from genetic modification of the Dahl S rat. Previously, we demonstrated that the S.SHR(11) rat fed a 0.3% NaCl diet exhibits earlier onset of kidney injury, a greater decline in kidney function compared to the Dahl S rat despite having similar blood pressure, thus providing a better model to test potential therapeutic interventions. Rats (7 -18 weeks old) were divided into two groups: the treatment group that received BD (20%) for 10 weeks via drinking water and controls on ad libitum water and both maintained on a low-salt rodent chow (Teklad 7034, 0.3% NaCl; n=5-6/group). Systolic blood pressure was measured after 9 weeks by tail-cuff plethysmography. After 10 weeks of BD treatment, 24h urine was collected and tissues were harvested. Treated rats were smaller than controls (330.2 ± 14.2 vs. 449.8 ± 22.9 g, p= 0.001). Urine excretion rate was lower in treated rats (11.3± 1.1 vs. 19.6 ± 3.8 ml/day, p=0.047) whereas kidney weight normalized to body weight was higher in this group (0.95 ± 0.04 vs. 0.77 ± 0.03 %, p=0.011). BD did not lower systolic blood pressure (157.0 ±14.0 vs. 163.9 ±14.6 mmHg, p=0.740). Proteinuria was diminished in the treated group, although not significant (135 ± 51 vs. 311 ± 67 mg/day, p= 0.064). Renal fibrosis (7.6 ± 0.61 vs. 9.4 ± 0.95 %, p=0.139), plasma creatinine (0.46 ±0.03 vs. 0.49 ± 0.01 mg/dL, p=0.466), and creatinine clearance normalized to kidney weight (0.57 ±0.05 vs. 0.67 ± 0.02 ml/min, p= 0.138) were not changed by treatment. Blood urea nitrogen was similar between groups (30.7 ± 2.57 vs. 27.4 ± 2.25mg/dL, p= 0.367). The current data demonstrate that BD does not mitigate hypertension nor improve renal function in male S.SHR(11) rats suggesting potential sex differences in the antihypertensive effects of BD. However, weight loss which has been associated with ketogenic interventions such as BD was still observed in this study.
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