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Molecules , 26, Ahangarpour, A. The results were expressed as µmol equivalents of FeSO 4 per mL. To investigate possible metabolic pathways of ASE phenolic compounds, analyses of plasma and urine metabolite were performed Table 3.

On the other hand, 3. We developed an in vitro model of uremia by incubating human tubular HK2 cells with two major uremic toxins at concentrations found in patients with end-stage renal disease.

Also, we evaluated the effect of ASE treatment in HK-2 cells in the presence of uremic toxins Indoxyl sulfate IS and p-Cresyl sulfate p-CS on fibrotic biomarker expression Fig.

Incubation of HK2 cells with IS and p-CS significantly increased the expression of pro-fibrotic genes α-SMA 3. Treatment with ASE prevents the expression of profibrotic genes in human tubular cells exposed to uremic toxins.

Human tubular cells HK2 were incubated for 16 h with two major uremic toxins, p-Cresyl sulfate p-CS and indoxyl-sulfate IS at concentrations found in patients with end-stage renal disease and µM for P-CS and IS, respectively and expression of pro-fibrotic gene expression was evaluated.

Gene expression of Collagen 1α Col-1α A , transforming growth factor β1 TGF-β1 B , connective tissue growth factor CTGF C and α-smooth muscle actin α-SMA D , All gene expressions were normalized to the expression of glyceraldehydePhosphate Dehydrogenase Gapdh.

Epidemiological studies suggest that consumption of phenolic compounds can reduce the incidence of chronic diseases such as CKD, possibly owing to the bioactivity exerted by these compounds and other phytochemicals that act synergistically 31 , 32 , We therefore hypothesized that a polyphenol-rich extract from Açaí could be used as a potential strategy to minimize CKD burden in adenine-fed mice.

Previous studies have shown that ASE exhibits many beneficial biological effects. ASE has potent antioxidant and anti-inflammatory activities in vitro as well as in vivo in experimental models of inflammation 34 , 35 , ASE further attenuates endothelial dysfunction and diminishes oxidative and inflammatory burden in endothelial cells 17 , Chronic administration of ASE improves aerobic physical performance in rats by increasing vascular and mitochondrial function ASE exerts an antihypertensive effect to prevent endothelial dysfunction and vascular remodeling in hypertensive rats ASE administration was also proved to prevent insulin resistance and hepatic steatosis in a murine model of obesity 15 , However, to the best of our knowledge, the effect of ASE on kidney disease has not been explored.

The present study demonstrates that ASE could decrease renal damage in mice with adenine induced renal failure mainly through its anti-fibrotic and antioxidant properties.

In the current investigation, renal failure was induced in mice using an adenine diet, a model widely known to instigate tubulointerstitial damage. After intestinal absorption, adenine is metabolized to 2,8-dihydroxyadenine, which crystalizes and precipitates in renal proximal tubules.

Consequently, tubular occlusion and local injury occur, which leads to inflammation of the tubular epithelium, tubulointerstitial fibrosis and renal dysfunction 38 , 39 , In agreement with previous reports, renal failure was successfully established in this experimental model, as evidenced by increased plasma urea concentration and proteinuria 20 , 41 , Moreover, polyuria was found in CKD mice, as evidence of reduced capacity to concentrate urines and leading to a compensatory increase in water intake.

Our data showed that chronic administration of ASE decreases the high levels of plasma urea and proteinuria induced by adenine feeding.

The histological tubular atrophy score showed that ASE decreased the extension of tubular damages. We further investigated the expression and urinary excretion of common biomarkers of tubular injury such as KIM-1 and NGAL.

KIM-1 is recognized as a sensitive and powerful biomarker of kidney injury 43 , 44 , Expression of KIM-1 and urinary concentrations of both KIM-1and NGAL were increased in mice fed with adenine and decreased by chronic supplementation with ASE.

CKD is often associated with tubulointerstitial fibrosis, resulting in the loss of nephrons, which are the functional units of the kidney The extension of renal fibrosis is regarded as a cornerstone in the progression of renal disease as it is a common hallmark of many renal diseases leading to renal failure.

Adenine mice exhibited extensive areas of fibrosis as evidenced histologically through Sirius red staining and supplementation with ASE successfully mitigated this effect.

Likewise, we found a remarkably higher collagen deposition in renal tissue from CKD mice compared to the control groups, as well as an increased expression of Col1a. Epithelial to mesenchymal transition EMT is a major step in the development of renal fibrosis 46 and TGF- β1 was shown to play a central role in this process 47 , We noticed an increase of both TGF-β1 gene expression and TGF-β1 protein abundance in kidney from CKD animals.

Importantly, ASE promoted a protective effect by mitigating these deleterious processes, which demonstrates a potential role in offering protection from renal fibrosis and preventing renal dysfunction, as previously described in hypertensive 49 and diabetic rats Taken together, these observations suggest that ASE can prevent renal damage in mice fed with adenine and improve kidney function.

The beneficial effects of ASE might be largely related to the inhibition of tissue fibrosis through the modulation of TGF-β1 secretion.

The progression of kidney fibrosis is intimately associated with oxidative stress. Indeed, TGF-β1 causes oxidative stress in the kidney through activation of NADPH oxidases 51 , 52 , 53 that further sustains the conversion of fibroblasts to myofibroblasts i.

the EMT. To investigate oxidative stress in the kidney, lipid peroxidation and the measurement of carbonylation of proteins were measured. Increased MDA and carbonylated protein concentrations in renal tissue from CKD mice unambiguously evidenced the occurrence of oxidative damage; in contrast, ASE accomplished to improve this deleterious effect in CKD mice by diminishing both biomarker levels, therefore preserving cellular function.

ASE further reduced the urinary excretion of 8-OH-dG, a common by-product of oxidative insult to DNA. The possible mechanisms of ASE could be related to the modulation of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase or possibly act as a scavenger of reactive species, as reported in our previous studies 18 , 49 , The assay of plasma total polyphenol contents and total antioxidant capacity using FRAP assay supports this view see Fig.

Indeed, renal failure in mice was associated with a decrease in plasma polyphenol content and a reduced antioxidant capacity. Both parameters were restored by daily supplementation with ASE polyphenols, and there was a good association between these two parameters see Fig.

Modulation of oxidative stress by ASE, whatever the mechanism involved, could have led to the reduction of kidney fibrosis. It is well documented that CKD in rodents promotes metabolic dysfunctions culminating in weight loss, adipose tissue depletion and ectopic lipid redistribution ASE further attenuated adipose tissue depletion in CKD see Table 1 , suggesting that it improves the nutritional status of the animals i.

Uremic toxins are deleterious compounds that accumulate in patients with renal failure as a result of decreased renal clearance Among uremic toxins, protein bound uremic toxins PBUTs such as IS and p-CS are the more noxious owing to their poor removal by common dialysis methods.

PBUTs were described as major contributors to the progression of renal failure and potent promotor of renal fibrosis To evaluate the ability of ASE to prevent PBUT-induced fibrosis, a cellular model of uremia was implemented.

Human renal tubular cells were exposed to p-CS and IS at concentrations found in patients with renal failure ASE blocked the PBUT-induced expression of pro-fibrotic genes, suggesting that part of the nephroprotective effect of ASE could result from prevention of toxicity of uremic toxins on renal tissues.

Such compounds belong to the subclass of flavanols, whose main metabolites are proanthocyanidins We observed that the consumption of ASE resulted in the urinary excretion of catechin and hippuric acid, vanillic acid, 3. However, the excretion of these compounds occurred differently for Control and CKD mice.

Mice from the Control group that consumed ASE showed greater excretion of catechin and vanillic acid compared to CKD mice that also received ASE. These compounds were possibly differentially metabolized by the intestinal microbiota of CKD mice and originate by-products that were not detected in our study.

Indeed, dysbiosis i. Phenolic compounds may undergo several distinct metabolic pathways and biotransformation steps by intestinal microbiota and host, including hydrolysis, conjugation by phase II enzymes, glucuronidation, demethylation and reduction reactions.

Moreover, some of these steps may be altered by disrupted microbiota in CKD, impairing polyphenol biotransformation 56 , In contrast, CKD mice that received ASE showed greater excretion of 3.

We emphasize that 3. This observation suggests a change in the composition of the colonic microbiota in CKD, favoring the growth of proteolytic bacteria, particularly uremic toxin producing species In both groups, hippuric acid HA was found to be the main metabolite in the urine; in fact, HA is one of the main phenolic acids excreted after the consumption of flavanols However, the concentration of this metabolite was two-fold higher in the plasma of CKD mice.

It is noteworthy that this phenolic acid is considered as an uremic toxin because it can accumulate in the plasma of renal patients and promote toxic effects including neurological symptoms, metabolic acidosis, left ventricular hypertrophy, endothelial dysfunction, and glomerular sclerosis 60 , 61 , As with the findings of our study, HA showed higher concentration in the plasma of uremic mice; on the other hand, urinary excretion of this metabolite was similar compared to the Control group The authors suggest that this phenomenon is related to dysbiosis and results in a higher load of glomerular filtrate, restoring the excretion rate to normal levels.

Dysbiosis has often been associated with CKD and is characterized by qualitative and quantitative changes in the host microbiome profile, followed by changes in the protective function of the intestinal barrier. One of the most relevant changes in the CKD microbiome profile is a higher prevalence of proteolytic uremic solute producing bacteria and enzyme producing bacteria such as urease and uricase.

Dysbiosis is related to renal dysfunction, increased cardiovascular risk in CKD, uremic toxicity and inflammation 63 , 64 , Finally, we point out that changes in the intestinal microbiota may affect the metabolism of different components from diets, for example, phenolic compounds, and this fact may be responsible for individual variations in homeostasis and the effects exerted by different compounds, as reported in the present study.

This study, however, has some limitations. First, the adenine mouse model used in the present study mainly mimics tubulopathies that are not the most common causes of kidney failure in humans. Thus, further studies with other models of kidney failure, e.

The antihypertensive activity of ASE as previously demonstrated in 2K-1C rats could have contributed to nephroprotection, as found in the present study. Since blood pressure measurements were not performed, we cannot rule out this hypothesis.

Taking all results together, our data demonstrate that ASE could improve the treatment of renal failure through its antifibrotic and antioxidant activities.

The reno-protective effect of ASE could be related to the inhibition of TGF- β1 pathway. CKD mice receiving ASE presented a distinct metabolite profile compared to the control mice receiving ASE. This result suggests different metabolization routes of phenolic compounds of ASE in vivo.

Supplementation with Açai products might be an interesting nutritional strategy to improve the progression of kidney disease towards renal failure.

Further studies are needed, however, to evidence this effect in patients with kidney disease. The data produced during the current study and the specific reagents such as ASE could be made available from the corresponding author upon reasonable request. Webster, A. Chronic kidney disease.

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Heliyon 6 , e e Xavier, G. Inhibitory effect of catechin-rich açaí seed extract on LPS-stimulated RAW Login View Cart 0. Staying Healthy Newsletter In the news: Nuts Linked to Kidney Health Polyphenols Help Gut. In the news: Nuts Linked to Kidney Health Polyphenols Help Gut. Eating Nuts Tied to Better Kidney Health In chronic kidney disease CKD , the kidneys become impaired over time and less able to cleanse the blood of toxic waste and extra fluid.

Dietary Polyphenols May Help Prevent Inflammation in Elderly Via Gut Microbiota Researchers from the University of Barcelona have shown that a diet high in polyphenols can support micro-organisms that produce compounds important to our health.

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Acta Pharmacologica Sinica 43 4 — Xiao T, Guan X, Nie L, Wang S, Sun L, He T, et al. Green tea is among the most popular beverages in China. Green tea polyphenols GTPs have been proven to have therapeutic effects on organ damage induced by heavy metal exposure. However, few studies have reported on GTP-relieving DEHP-induced kidney damage.

The renal function of mice and renal tissue histopathology of each group were evaluated. The renal tissues of mice in the model, treatment, and control groups were analyzed using high-throughput sequencing. We calculated the differentially expressed microRNAs miRNAs and messenger RNAs mRNAs using the limma R package, the CIBERSORT algorithm was used to predict immune infiltration, the starBase database was used to screen the miRNA-mRNA regulatory axis, and immunohistochemical analyses were performed to verify protein expression.

Results: GTP alleviated the deterioration of renal function, renal inflammation and fibrosis, and mitochondrial and endoplasmic reticulum lesions induced by DEHP in mice. Differential immune infiltrations of plasma, dendritic, T, and B cells were noted between the model and treatment groups.

We found that three differentially expressed miRNAs mmu-miRp, mmu-miRp, and mmu-miRp , three differentially expressed mRNAs Ddit4, Dusp1, and Snx18 , and three differentially expressed proteins Ddit4, Dusp1, and Snx18 played crucial roles in the miRNA-mRNA-protein regulatory axes when GTPs mitigate DEHP-induced kidney damage in mice.

Conclusion: GTP can alleviate DEHP-induced kidney damage and regulate immune cell infiltration. We screened four important miRNA-mRNA-protein regulatory axes of GTP, mitigating DEHP-induced kidney damage in mice. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.

filter your search All Content All Journals American Journal of Nephrology. Advanced Search. Skip Nav Destination Close navigation menu Article navigation. Volume 55, Issue 1. Article Navigation. Research Articles September 21 Green Tea Polyphenols Alleviate Kidney Injury Induced by Di 2-Ethylhexyl Phthalate in Mice Subject Area: Nephrology.

Heng Shi ; Heng Shi. a Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, China.

b Department of Gastroenterology, The Central Hospital of Shaoyang, Shaoyang, China.