Basic nutritional investigationEicosapentaenoic acid prevents salt sensitivity in diabetic rats and decreases oxidative stress
Introduction
Diabetes mellitus (DM) is a major cause of death and disability worldwide and a strong risk factor for cardiovascular disease. In particular, diabetic nephropathy (DN) remains a significant problem despite efforts to limit its impact on end-organ damage. In a complex milieu where no single treatment can halt DN progression, interactions have been found between metabolic and hemodynamic factors involved in the development of renal lesions in patients with DM [1].
Salt sensitivity (SS), defined as an increase of >10% of blood pressure and secondary to sodium load, is one of the initial changes observed during the development of hypertension in DM. According to the classic concept by Guyton and Coleman [2], high salt intake increases a circulating volume, which leads to an increase in renal perfusion pressure, immediately followed by an increase in natriuresis that restores the circulating volume. This pressure-natriuresis mechanism prevents an increase in blood pressure (BP) that could arise from a transient increase of circulating volume. Thus, the deterioration of this mechanism increases the circulating volume and blood pressure leading to hypertension [3].
Several studies have reported the infiltration of macrophages and proinflammatory cells in the kidney at different stages of DN. The inflammatory infiltrate produces reactive oxygen species (ROS) and proinflammatory cytokines, which lead to an upregulation of chronic systemic inflammation and mediate DN progression [4]. As a consequence of the inflammation, various cytokines and acute phase proteins are released to augment or attenuate the inflammatory response. The main inflammatory cytokines involved in the development of DN are interleukin (IL) 6, as well as IL-1β, IL-18, and tumor necrosis factor-α that may contribute to the progression of renal injury, either directly or indirectly [5]. Thus, chronic inflammation of kidney tissue contributes to DN, not only as a consequence of a direct effect of proinflammatory mediators on cellular signaling, but also by creating a state of oxidative stress, and sodium reabsorption is increases under these conditions [6].
In recent years, substantial evidence has implicated nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-sensitive transcription factor, in inflammation and associated disorders. In this setting, the therapeutic potential of Nrf2 activation in DM as relating to the control of oxidative stress has been described [7,8]. Chronic inflammation and oxidative stress contribute not only to DN development, but also to increased sodium reabsorption and enhancing circulatory volume [6], a condition associated with abnormal pressure natriuresis. It is widely believed that abnormal pressure natriuresis is the initial abnormality observed before the fully development of hypertension [9]. In this setting, the relative contribution of interindividual differences on the basis of genetic background, nutrition, physical activity, and other environmental factors has not been fully elucidated.
Understanding how these factors interact is necessary to tackle the global burden of hypertension triggered by DM. In particular, the pathophysiological effects of diets have drawn attention in response to the increasing worldwide adoption of the Western diet and the accompanying increase in the incidence rate of obesity, which is an associated outcome of DM [10]. Particularly, a high intake of ω-6 polyunsaturated fatty acids (PUFAs) and lower intake of ω-3 PUFAs, which is typical of a Western diet, exert several functions that play significant roles in inflammation, metabolism, and the regulation of intracellular processes. The supplementation of eicosapentaenoic acid (EPA 20:5, ω-3) especially is an important regulator of cardiovascular health because of the decrease in the levels of markers and mediators of inflammation, such as cytokines interleukin-1β and tumor necrosis factor α [11]. Therefore, we hypothesized that nutritional supplementation with EPA 20:5 ω-3 prevents the increase of blood pressure owing to sodium load in rats with Type 2 DM (T2-DM) by decreasing renal oxidative stress via Nrf2 activation and decreasing IL-6 release.
Section snippets
Experimental design
Diabetic rats (eSS) are a stable strain derived from Wistar rats a model of T2-DM that is characterized by fasting hyperglycemia, glucose intolerance, hyperinsulinemia, and early hypertriacylglycerolmia. Diabetic symptoms in this model worsen with age as insulin release decreases and closely resembles T2-DM in adult humans. eSS rats were kindly provided by Professors Tarres and Martinez from the University of Rosario in Argentina [12]. Three-month-old male Wistar (healthy control) or eSS rats
HNaD increased and EPA prevented blood systolic pressure in diabetic rats
Wi rats weighed 37% more than eSS rats of the same age; however, no difference was observed in basal SBP. As expected, rats with T2-DM showed higher HbA1c levels (+43%) compared with those in the Wi group. Additionally, the eSS group showed higher postprandial glucose, Chol, and TAG levels. All rats with T2-DM that were treated had lower serum lipid levels compared with those in the eSS group. Renal functions were similar between the groups. Table 1 shows the physiological parameters of each
Discussion
Our results show that EPA treatment minimized inflammation and oxidative stress in rats with T2-DM through Nrf2 activation during sodium load, which are effects associated with less glomerular sclerosis and less interstitial fibrosis. This effectively prevented SS observed in untreated diabetic rats and was independent of glucose homeostasis because HbA1c levels did not change. Particularly, EPA supplementation prevented the deleterious outcome by improving endothelial function and preventing
Conclusions
Overall, this study provides compelling evidence that adequate ω-3 supplementation can minimize inflammation as well as oxidative stress through Nrf2 activation in T2-DM after Na overload. EPA effectively prevented SS observed in untreated diabetic rats independent of glucose homeostasis because the HbA1c levels did not change. In particular, EPA supplementation did not present any deleterious effect because EPA improved endothelial function and thus prevented increased blood pressure in DM
Acknowledgments
The authors are grateful to Mr. Ricardo Mattos (Facultad de Ciencias Médicas, Universidad Nacional de Córdoba) and Clarisa Lagares (Consejo Nacional de Investigaciones Científicas y Técnicas) for animal care. Néstor H. Garcia acknowledges the support from the Consejo Nacional de Investigaciones Científicas y Técnicas.
References (58)
- et al.
Diabetes as a risk factor for stroke in women compared with men: A systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes
Lancet
(2014) - et al.
An intracellular adrenomedullin system reduces IL-6 release via a NF-kB-mediated, cAMP-independent transcriptional mechanism in rat thymic epithelial cells
Cytokine
(2016) - et al.
Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension
Am J Clin Nutr
(2010) - et al.
Salt and hypertension: Is salt dietary reduction worth the effort?
Am J Med
(2012) - et al.
Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms
Can J Cardiol
(2018) - et al.
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis
Lancet
(2007) - et al.
GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
Cell
(2010) - et al.
Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice
J Nutr Biochem
(2016) - et al.
Omega 3 rich diet modulates energy metabolism via GPR120-Nrf2 crosstalk in a novel antioxidant mouse model
Biochim Biophys Acta Mol Cell Biol Lipids
(2019) - et al.
The Keap1-Nrf2 system and diabetes mellitus
Arch Biochem Biophys
(2015)
The green tea polyphenol (-)-epigallocatechin-3-gallate ameliorates experimental immune-mediated glomerulonephritis
Kidney Int
Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats
Life Sci
Long-term regulation of the circulation: Inter-relationship with body fluid volumes
Salt sensitivity and hypertension: A paradigm shift from kidney malfunction to vascular endothelial dysfunction
Electrolyte Blood Press
Anti-inflammatory therapy modulates Nrf2-Keap1 in kidney from rats with diabetes
Oxid Med Cell Longev
Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy
Cardiovasc Ther
Effects of reactive oxygen species on tubular transport along the nephron
Antioxidants
Bardoxolone methyl and kidney function in CKD with type 2 diabetes
N Engl J Med
Effect of redox modulating NRF2 activators on chronic kidney disease
Molecules
Pressure natriuresis and the renal control of arterial blood pressure
J Physiol
Targeting inflammation in the treatment of type 2 diabetes: Time to start
Nat Rev Drug Discov
n–3 fatty acids in cardiovascular disease
N Engl J Med
The eSS rat. A model of non-insulin-dependent human diabetes
Amer J Pathol
Statins reverse renal inflammation and endothelial dysfunction induced by chronic high salt intake
Am J Physiol Renal Physiol
Dietary Salba (Salvia hispanica L.) ameliorates the adipose tissue dysfunction of dyslipidemic insulin-resistant rats through mechanisms involving oxidative stress, inflammatory cytokines and peroxisome proliferator-activated receptor γ
Eur J Nutr
Increased dietary levels of α-linolenic acid inhibit mammary tumor growth and metastasis
Eur J Nutr
Salt sensitivity of blood pressure: a scientific statement from the American Heart Association
Hypertension
Salt sensitivity. Definition, conception, methodology, and long-term issues
Hypertension
Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension
J Hum Hypertens
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