Abstract P109: A Novel Murine Model Of Diet-induced Cholemia For Studies On The Gut-liver-kidney Axis In Blood Pressure Regulation

Bile acids (BA) are classically viewed as emulsifiers produced by the liver for aiding the absorption of fats in the gut. Accumulating evidence now recognizes BA as vasoactive agents capable of lowering blood pressure (BP). However, it remains unclear whether the ensuing hypotension can be associated with end-organ damage. To delineate the pathogenic role of BA in the gut-liver-kidney axis, we leveraged our prior finding that a subset of C57BL/6 mice developed cholemia ( i.e. , high circulating BA) when fed a diet supplemented with 7.5% inulin. Briefly, we challenged 4-week-old male mice (n=50) with the inulin diet for one week and identified the subset that developed cholemia (B6 BA ; n=6). Non-cholemic mice (B6; n=6) were maintained as control. Assessment on BP at 6 months of inulin feeding indicated that B6 BA mice (systolic BP: 107.6 ± 2.2 mmHg; diastolic BP: 78.6 ± 3.1 mmHg) are hypotensive relative to non-cholemic B6 mice (systolic BP: 139.8 ± 5.6 mmHg; diastolic BP: 109.0 ± 3.8 mmHg), which was accompanied by polydipsia (7.0 ± 0.4 ml/day in B6 BA vs 4.3 ± 0.2 ml/day water intake in B6), polyuria (2.5 ± 0.1 ml/day in B6 BA vs 1.2 ± 0.1 ml/day urine output in B6), and elevated urinary BA (28.5 ± 1.7 μM in B6 BA vs 3.3 ± 0.6 μM in B6) in B6 BA mice. B6 BA mice also excreted more urinary creatinine (50.4 ± 3.4 mg/dl in B6 BA vs 25.6 ± 1.3 mg/dl in B6), sodium (271.8 ± 20.1 μmol/day in B6 BA vs 103.0 ± 11.0 μmol/day in B6) and potassium (349.2 ± 16.7 μmol/day in B6 BA vs 128.7 ± 7.7 μmol/day in B6), which could be, in part, explained by their higher glomerular filtration rate (1209.0 ± 121.0 in B6 BA vs 681.2 ± 148.7 μl/min/100 g body weight in B6). Of note, B6 BA mice displayed renomegaly, interstitial nephritis, and bile casts in urine, as well as elevated renal transcripts (>2-fold increase relative to B6) for lipocalin 2, kidney injury molecule-1, tumor necrosis factor alpha, collagen type I α1 and endothelin-1. Taken together, these findings demonstrate that our mouse model of diet-induced cholemia presents with low BP and renal pathology. We envision that this model has notable advantages ( e.g. , ease in inducing cholemia, no early morbidity and tractable for long-term study), in lieu of the conventional bile duct ligation approach, for studying how BA regulate BP.