Korean J Physiol Pharmacol.  2020 Jul;24(4):319-328. 10.4196/kjpp.2020.24.4.319.

Activation of the renin-angiotensin system in high fructose-induced metabolic syndrome

• Kim M
• Do GY
• Kim I

• KMID: 2503325
• DOI: http://doi.org/10.4196/kjpp.2020.24.4.319

Abstract

High fructose intake induces hyperglycemia and hypertension. However, the mechanism by which fructose induces metabolic syndrome is largely unknown. We hypothesized that high fructose intake induces activation of the renin-angiotensin system (RAS), resulting in hypertension and metabolic syndrome. We provided 11-week-old Sprague–Dawley rats with drinking water, with or without 20% fructose, for two weeks. We measured serum renin, angiotensin II (Ang II), and aldosterone (Aldo) using ELISA kits. The expression of RAS genes was determined by quantitative reverse transcription polymerase chain reaction. High fructose intake increased body weight and water retention, regardless of food intake or urine volume. After two weeks, fructose intake induced glucose intolerance and hypertension. High fructose intake increased serum renin, Ang II, triglyceride, and cholesterol levels, but not Aldo levels. High fructose intake increased the expression of angiotensinogen in the liver; angiotensin-converting enzyme in the lungs; and renin, angiotensin II type 1a receptor (AT1aR), and angiotensin II type 1b receptor (AT1bR) in the kidneys. However, expression of AT1aR and AT1bR in the adrenal glands did not increase in rats given fructose. Taken together, these results indicate that high fructose intake induces activation of RAS, resulting in hypertension and metabolic syndrome.

Keyword

Fructose; Hypertension; Metabolic syndrome; Obesity; Renin-angiotensin system

Figure

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  Fig. 1 Effects of high fructose intake on body weight and biological parameters. Male Sprague–Dawley rats drank either water (control, n = 6) or water containing 20% fructose (fructose, n = 6) for two weeks. (A) Body weight was monitored for two weeks. High fructose intake promoted weight gain. Food intake, water intake, and urine volume were measured using metabolic cages. (B) High fructose intake did not affect food intake. (C) High fructose intake increased water intake. (D) Urine volume decreased in the fructose group. (E) Water retention increased in the fructose group. Data are presented as mean ± standard error of six rats (*p = 0.05, control vs. fructose).

• 

  Fig. 2 Effects of high fructose intake on systolic blood pressure (BP) and glucose tolerance. (A) Systolic blood pressure was measured using a tail-cuff method in control rats (n = 6) and rats drinking 20% fructose (n = 6) for a period of two weeks. High fructose intake induced hypertension. (B) Glucose tolerance tests (GTTs) were performed on rats at the end of the first week. (C) The corresponding area under the curve (AUC) values were obtained. (D) A second GTT was performed on rats at the end of the second week. (E) Corresponding AUC values were obtained. High fructose intake caused glucose intolerance. Data are presented as mean ± standard error of six rats (*p = 0.05, **p = 0.01, control vs. fructose).

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  Fig. 3 High fructose intake activated the renin-angiotensin system. Serum renin, angiotensin II (Ang II), and aldosterone (Aldo; expressed as pg per ml of serum) were measured in rats drinking 20% fructose for two weeks. High fructose intake increased (A) renin and (B) Ang II levels. (C) High fructose intake did not affect Aldo levels. (D) Blood chemistry. Data are presented as mean ± standard error of six rats (*p = 0.05, **p = 0.01, control vs. fructose). ALT, alanine transaminase; AST, aspartate transaminase; HDLC, high density lipoprotein cholesterol; LDLC, low density lipoprotein cholesterol.

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  Fig. 4 Effects of high fructose intake on the expression of renin-angiotensin system (RAS) genes in the lungs and liver. RAS-related gene expression was quantified by RT-qPCR. High fructose intake increased the expression of angiotensinogen (Agt) in the liver (A) and angiotensin-converting enzyme (Ace) in the lungs (B). The graphs show the mean ± standard error of three independent experiments (*p = 0.05, **p = 0.01, control vs. fructose).

• 

  Fig. 5 Effects of high fructose intake on the expression of renin-angiotensin system (RAS) genes in the kidney. Representative images of kidneys and adrenal glands are shown from rats drinking either water (control, n = 6) or 20% fructose (fructose, n = 6). (A) Representative gross images of kidneys and adrenal glands are shown for control and fructose-intake rats. RAS-related gene expression of was quantified by RT-qPCR. Intake of 20% fructose increased the expression of renin, angiotensin II type 1a receptor (AT1aR), angiotensin II type 1b receptor (AT1bR), and angiotensin II type 2 receptor (AT2) in the kidneys (B–E). (F) Kidneys sections were stained with H&E or trichrome. Renin, AT1R, and angiotensin II (Ang II) proteins were detected by immunohistochemistry. JGA, juxtaglomerular apparatus. The graphs show the mean ± standard error of three independent experiments (*p = 0.05, **p = 0.01, control vs. fructose).

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  Fig. 6 Effects of high fructose intake on the expression of renin-angiotensin system (RAS) genes in the adrenal glands. (A, B) RAS-related gene expression was quantified by RT-qPCR. However, high fructose intake did not affect the expression of angiotensin II type 1a receptor (AT1aR) or angiotensin II type 1b receptor (AT1bR) in the adrenal glands. Representative images show adrenals from rats drinking either water (control, n = 6) or water containing 20% fructose (fructose, n = 6). (C) Adrenal gland sections were stained with H&E. AT1R and angiotensin II (Ang II) proteins were detected by immunohistochemistry. The graphs show the mean ± standard error of three independent experiments (*p = 0.05, **p = 0.01, control vs. fructose).

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  Fig. 7 Schematic diagram. Eleven-week-old male Sprague–Dawley rats were fed either a chow diet (control, n = 6) or a chow diet supplemented with 20% fructose (fructose, n = 6) in drinking water for two weeks. High fructose intake induced metabolic syndrome and activated renin-angiotensin system (RAS). Ang, angiotensin; ACE, angiotensin-converting enzyme.

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