Increased Methylglyoxal Formation with Upregulation of Renin Angiotensin System in Fructose Fed Sprague Dawley Rats

Indu Dhar,Lingyun Wu,Kaushik M Desai,Arti Dhar,Nick Ashton

doi:10.1371/journal.pone.0074212

Abstract

The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.

Highlights

High dietary carbohydrates, increasing type 2 diabetes and obesity, and the associated hypertension and cardiovascular diseases are major health issues globally [1,2,3]
Treatment of SD rats with a high fructose diet for 16 weeks caused a significant increase in the blood pressure, which was attenuated by the MG scavenger metformin (Fig. 1A)
Chronic treatment of SD rats with fructose for 16 weeks significantly elevated aortic adrenergic a1D receptor, angiotensin AT1 receptor and angiotensin II (Ang II) protein and mRNA, which were attenuated by co-treatment with metformin (Fig. 2)

Summary

Introduction

High dietary carbohydrates, increasing type 2 diabetes and obesity, and the associated hypertension and cardiovascular diseases are major health issues globally [1,2,3]. The explosive increase in type 2 diabetes in the past 2–3 decades has been attributed to high dietary carbohydrates, especially fructose, combined with a sedentary lifestyle. Compared to the general population the risk of high blood pressure (BP, systolic BP$140 mmHg or diastolic BP$90 mmHg) is four times higher for people with diabetes [4]. The Western diet has high fructose content, mainly in the form of high fructose corn syrup, which has been proposed to induce hypertension [1,3]. High fructose diet-fed Sprague-Dawley (SD) rats have been widely used as a model of insulin resistance and these rats develop hypertension [5,6]

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Conclusion