Common Metabolites in Two Different Hypertensive Mouse Models: A Serum and Urine Metabolome Study

Abstract

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension's pathophysiology with respect to metabolites. We utilized two common mouse models of experimental hypertension: L-arginine methyl ester hydrochloride (L-NAME)/high-salt-diet-induced hypertension (LSHTN) and angiotensin II induced hypertension (AHTN). To identify common metabolites that were altered across both models, we performed untargeted global metabolomics analysis in serum and urine and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A total of 41 serum metabolites were identified as being significantly altered in any hypertensive model compared to the controls. Of these compounds, 14 were commonly changed in both hypertensive groups, with 4 significantly increased and 10 significantly decreased. In the urine, six metabolites were significantly altered in any hypertensive group with respect to the control; however, none of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies of the newly identified metabolites from this untargeted metabolomics analysis may lead to a greater understanding of the association between gut dysbiosis and hypertension.

Keywords: angiotensin II; hypertension; metabolomics; microbial metabolites; salt.

Figure 1

Systemic blood pressures (SBP) of control mice and mice with L-NAME/high-salt-diet-induced hypertension (LSHTN) or angiotensin II induced hypertension (AHTN). * indicates p < 0.05 by ANOVA, (n = 3).

Figure 2

Metabolomics data of serum showing segregation of hypertensive groups from control. Principal components analysis (PCA) plot of metabolites present in the serum based on untargeted metabolomics demonstrated visible segregation based on peak intensity values of metabolites in both LSHTN and AHTN mice when compared to control mice, (n = 3).

Figure 3

Common serum metabolites increased or decreased significantly in both LSHTN and AHTN mice compared to control mice. Serum metabolites that were significantly increased in both hypertensive groups are shown in (A). Serum metabolites that were significantly decreased in both hypertensive groups are shown in (B). * indicates p < 0.05 by one-way ANOVA. Data are plotted as fold changes in log transformed values of the normalized peak intensity values, (n = 3).

Figure 4

Metabolomics data of urine showing intermixed results of the hypertensive groups with the control group. PCA plot of metabolites present in the urine based on untargeted metabolomics demonstrated no visible segregation among metabolites of LSHTN and AHTN mice when compared to control mice, (n = 3).