Sorbitol Levels Linked to Hypertension from High Salt and Fructose Diets

High salt (HS) diet and fructose are consumed in excess in Western societies. Convenience foods, such as soft drinks, contain high levels of both fructose and HS and are linked to the development of salt-sensitive hypertension (SS-HTN) and the development of chronic kidney disease (CKD). However, the mechanisms linking fructose, HS and these diseases are not yet understood. There are also data suggesting that specific sugars, such as sorbitol, may be detrimental to the kidney and can be produced via the metabolism of fructose and glucose. Here, we hypothesized that consumption of fructose with HS diet (HSD) may lead to SS-HTN via accumulation of renal sugar. Male and female C57BI/6 mice (10 weeks old, n=4-6) were treated with vehicle (veh), fructose (10% in drinking water), or fructose plus HSD (4% chow) for 28 days. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography. Morphometry data, such as cardiac hypertrophy, was collected, along with kidney tissue for mass spectrometry (LC/MS). We then analyzed sugar metabolites (glucose, sorbitol, mannose, mannitol and fructose). All data are presented by mean±standard deviation. We first analyzed blood pressure and observed an increase in systolic blood pressure (SBP) in fructose+HSD fed male mice 28 days (130.2±5.6mmHg fructose+HSD vs. 120.1±6.6 fructose vs. 110.5±4.6mmHg veh; p<0.01). Interestingly, female mice seem protected from increased blood pressure in this model. We additionally observed no changes in cardiac hypertrophy. To determine mechanism, sugar metabolites were assessed. All sugars were increased in fructose + HSD-fed mice as compared to veh (p<0.01, male&female). However, male mice had significantly increased renal sorbitol levels when fed fructose+HSD, as compared to fructose alone (1.5 fold change increase; p<0.01). However, female mice had increased mannitol (2.0 fold change increase; p<0.001), suggesting that metabolic increases in mannitol following fructose+HSD may be protective. Here, we show that fructose+HSD increases SBP in male mice, with a corresponding increase in renal sorbitol levels. Yet, female mice were protected and showed an increase in mannitol. Together, these data suggest that there are differential sugar metabolism pathways in male vs . female mice, which may be activated when fructose is consumed together with HSD. This process may lead to accumulation of sugar molecules which can either contribute to SS-HTN or prevent the development of SS-HTN.