1,3‐Butanediol Ameliorates Hypertension and Suppresses the Progression of Kidney Disease in Rats
Authors: Ishimwe Jeanne A. , Garrett Michael R. , Sasser Jennifer M. 
Published: April 2020

37 million people in the United States are estimated to have chronic kidney disease (CKD). Hypertension (HTN), a condition affecting one‐third of Americans, is the second leading risk factor for developing kidney disease. A recent study reported that increasing circulating levels of the ketone body beta‐hydroxybutyrate (BHB) levels by administration of its precursor 1,3‐Butanediol (BD) decreased salt‐induced hypertension in male Dahl salt‐sensitive (S) rats. However, the effect of BD on CKD has not been investigated. We have previously characterized a rat strain, S.SHR(11), generated from genetic modification of the Dahl S rat to develop accelerated renal disease. The S.SHR(11) exhibits a greater decline in kidney function, a high degree of medullary fibrosis and a significant increase in renal vascular medial hypertrophy compared to the Dahl S rat despite having similar blood pressure. The present study tests the hypothesis that 1,3‐Butanediol attenuates hypertension and progression of kidney disease in female S.SHR(11). Rats were divided into two groups: the S.SHR(11)+ BD (20%) for 10 weeks via drinking water and S.SHR(11)+CON that were kept on ad libitum water. Both groups were maintained on a normal rodent chow (Teklad 7034, 0.3% NaCl; n=12–14/group). Blood pressure was measured every 3 weeks by tail‐cuff plethysmography. After 10 weeks of BD treatment, 24h urine was collected and animals were euthanized, and tissues harvested for further tests. Statistical comparisons between groups were done by Student t‐test. Data are expressed as mean ±SEM and p<0.05 was considered for statistical significance. We confirmed the activity of the treatment by measuring plasma BHB levels which were greater in the treated group (0.24±0.078 vs. 0.07±0 mM, p=0.06). BD significantly lowered systolic pressure after 6 weeks (150±7 vs. 171±6 mmHg, p=0.04) and after 9 weeks the treatment group demonstrated an even greater reduction in BP (137±7 vs. 170±5 mmHg, p=0.003). Renal injury traits were evaluated in these animals between control and treatment groups. The treated group had significantly lower proteinuria (109±18 vs. 224 ±54 mg/day, p=0.04), plasma creatinine (0.43±0.013 vs. 0.49±0.024 mg/day, p=0.03) and significant reduction in renal fibrosis (6.6±0.9 vs. 10.3±0.8 %, p=0.006). We further evaluated two additional markers of renal injury: kidney injury molecule‐1 (KIM‐1) and neutrophil gelatinase‐associated lipocalin (NGAL). Urinary excretion rates of both KIM‐1 (14.74±1.99 vs. 20.42±2.10 pg/day, p=0.06) and NGAL (9326±1713 vs. 24863±12733 pg/day, p= 0.23) trended to be lower in the treated group compared to controls. Furthermore, the group that received treatment had significantly smaller spleens (0.74±0.02 vs. 0.85±0.01 g, p=0.0007) which may suggest a reduction in inflammation. The current data demonstrate that BD lowers blood pressure even in females, beyond salt‐induced HTN and could be a novel therapeutic target for the treatment of CKD.Support or Funding InformationThis work was supported by the National Institutes of Health under award numbers R01HL134711 (J. M. Sasser) and R01HL137673 ( M. R. Garrett)