A Blueberry-Enriched Diet Improves Renal Function and Reduces Oxidative Stress in Metabolic Syndrome Animals: Potential Mechanism of TLR4-MAPK Signaling Pathway

Abstract

BackgroundMetabolic syndrome (MetS) is characterized by a cluster of health factors that indicate a higher risk for cardio-renal diseases. Recent evidence indicates that antioxidants from berries are alternative to attenuate oxidative stress and inflammation. We tested the hypothesis that inflammation-induced renal damage is triggered by the activation of TLR4, and subsequent modulation of redox-sensitive molecules and mitogen-activated protein kinase (MAPK) pathway.MethodsFive-week old lean and obese Zucker rats (LZR and OZR) were fed a blueberry-enriched diet or an isocaloric control diet for 15 weeks. A glucose tolerance test and acute renal clearance experiments were performed. Gene and protein expression levels for TLR4, cytokines and phosphorylation of ERK and p38MAPK were measured. Kidney redox status and urinary albumin levels were quantified. Renal pathology was evaluated histologically.ResultsControl OZR exhibited lower glucose tolerance; exacerbated renal function parameters; increased oxidative stress. Gene and protein expression levels of TLR4 were higher and this was accompanied by increased renal pathology with extensive albuminuria and deterioration in antioxidant levels in OZR. In addition, OZR had increased phosphorylation of ERK and p38MAPK. Blueberry-fed OZR exhibited significant improvements in all these parameters compared to OZR.ConclusionTLR4-MAPK signaling pathway is a key to the renal structural injury and dysfunction in MetS and blueberry (BB) protect against this damage by inhibiting TLR4.SignificanceThis is the first study to put forth a potential mechanism of TLR4-induced kidney damage in a model of MetS and to elucidate a downstream mechanism by which blueberry exert their reno-protective effects.

Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells

“…Total RNA isolation, cDNA synthesis and RT-PCR were performed as previously described [16,35]. Semi-log amplification curves were evaluated by the comparative quantification method (2 À ΔΔct ), and GAPDH or 18s RNA was used for normalization of all reported gene levels.…”

“…Total ROS and superoxide production rates were measured in NRK52E cells via EPR spectroscopy as previously described [16,[35][36][37][38]. The term 'total ROS' represents all ROS; however, the major sources trapped by the spin trap used are superoxide, hydrogen peroxide, and hydroxyl radical, with other species as minimal contributors.…”

Illumination from light-emitting diodes (LEDs) disrupts pathological cytokines expression and activates relevant signal pathways in primary human retinal pigment epithelial cells

“…4). Oxidative stress is known to activate the MAPKs, the most ubiquitous signal transduction systems, which play important roles in modulating the survival, apoptosis and inflammatory response (McCubrey et al, 2006;Nair et al, 2014). NF-kB is present in the cytoplasm in an inactive complex.…”

Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

“…A number of animal studies have demonstrated the anti-diabetic effects of blueberry anthocyanins (Figure 1). Obese rodents that were diet-induced and genetically manipulated consumed a 45%–60% high fat-diet (HFD) with blueberries for 3–12 weeks and their insulin resistance (i.e., assessed using the homeostatic model assessment-estimated insulin resistance (HOMA-IR)) [18,21] and glucose tolerance (assessed using the glucose tolerance test) [15,16,17,18,20] were improved. Similar results were observed when an intraperitoneal insulin tolerance test (ITT) was used to measure insulin sensitivity.…”

“…The scientific evidence supporting the anti-diabetic health benefits of blueberries is growing. Pre-clinical [14,15,16,17,18,19,20,21] and clinical [22,23,24,25] studies have found improvements in insulin resistance and glucose tolerance after blueberry consumption in obese and insulin-resistant rodents and humans. For many years, increased consumption of blueberries has been a folk remedy in Canada for treating T2DM [26].…”