Fructose Consumption Increases Blood Pressure and Induces Changes in Renal Microvascular Function

Abstract

A drastic increase in fructose consumption over recent decades has been paralleled by a growing prevalence and incidence of hypertension, along with comorbidities, such as diabetes, renal failure, and cardiovascular disease. High fructose corn syrup is a commonly found ingredient in the Western diet. However, the use of fructose as a sweetener has been shown to promote salt‐sensitive hypertension. The mechanisms by which fructose induces an increase in blood pressure and its effect on renal microvascular function are not completely understood. The goal of this study was to understand the mechanisms that lead to fructose‐induced impairment in renal microvascular function and its relation to the development of hypertension. Salt‐resistant Sprague Dawley rats (8 weeks old) were kept on a low salt (LS; 0.4% NaCl) with or without addition of 20% fructose (FT) to the drinking water provided ad libitum. After two weeks control and FT‐treated groups were switched to a high salt (HS; 8% NaCl) diet. Blood pressure was monitored with surgically implanted telemetry devices. Electrolyte balance and changes in renal function were analyzed among experimental groups using urinary (24 hrs collections) and plasma samples. After two weeks on HS, animals were euthanized, and renal microvessels were isolated to assess renal smooth muscle cell (SMC) excitability. We found that FT‐treated animals experienced elevated systolic blood pressure at LS to compare with control, and this difference were significantly higher in HS‐treated groups (107 ± 3 vs 113 ± 3, and 114 ± 4 vs 131 ± 5, mmHg; LS vs LS+FT, and HS vs HS +FT, correspondingly). Furthermore, these changes inversely correlated with the shift in diuresis and electrolyte balance in HS‐treated animals (70 ± 15 vs 39 ± 15 ml/day, 284 ± 91 vs 123 ± 70 Na/Cre ratio, 36 ± 12 vs 14 ± 10 K/Cre ratio, 0.7 ± 0.4 vs 1.4 ± 0.3 Ca/Cre ratio, HS vs HS+FT correspondingly). No changes in albuminuria, compared with controls, were noted in any of the groups. Two‐photon microscopy analysis of the renal microvascular vasomotion revealed a decrease in amplitude of individual SMC Ca2+ activity at the resting, spontaneous state in both LS and HS FT‐treated groups. However, both amplitude and period of Ca2+ fluctuations in SMC was significantly increased when vessels were exposed to ET‐1 in HS+FT group. Moreover, the amplitude of ET‐1‐induced Ca2+ transient in FT‐treated animals were split into two distinct groups with either higher or lower amplitudes relative to control. Overall, renal microvessels exposed to FT revealed a significant decrease in spontaneous vasomotion, which is accompanying by high responsiveness to FT at the HS with significant decrease in frequency of spontaneous events. These effects further promote high sensitivity (above normal) to ET‐1 stimulation, cell damage and finally low responsiveness (below normal) in FT‐treated renal microvessels. In conclusion, these results indicate the detrimental effects of FT on intracellular Ca2+ homeostasis in SMC, renal microvascular function and blood pressure regulation under high dietary salt.Support or Funding InformationNational Institute of Health R35 HL135749 (to A.S.), Michael Keelan, Jr., MD, CVC Research Foundation Grant (to O.P.), and Advancing a Healthier Wisconsin Endowment (to J.D.I.)