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17 pages, 3877 KiB

Open AccessArticle

Pro-Inflammatory Effects of Indoxyl Sulfate in Mice: Impairment of Intestinal Homeostasis and Immune Response

by Shara Francesca Rapa, Francesco Prisco, Ada Popolo, Valentina Iovane, Giuseppina Autore, Biagio Raffaele Di Iorio, Fabrizio Dal Piaz, Orlando Paciello, Fuyu Nishijima and Stefania Marzocco

Int. J. Mol. Sci. 2021, 22(3), 1135; https://doi.org/10.3390/ijms22031135 - 24 Jan 2021

Cited by 26 | Viewed by 3379

Abstract

The intestines are recognized as the main source of chronic inflammation in chronic kidney disease (CKD) and, among other cells, macrophages are involved in modulating this process as well as in the impaired immune response which also occurs in CKD patients. In this [...] Read more.

The intestines are recognized as the main source of chronic inflammation in chronic kidney disease (CKD) and, among other cells, macrophages are involved in modulating this process as well as in the impaired immune response which also occurs in CKD patients. In this study, we evaluated the effect of Indoxyl Sulfate (IS), a protein bound uremic toxin poorly eliminated by hemodialysis, on inflammatory, oxidative stress and pro-apoptotic parameters, at the intestinal level in mice, on intestinal epithelial cells (IEC-6) and on primary murine peritoneal macrophages. C57BL/6J mice were treated with IS (800 mg/kg i.p.) for 3 or 6 h and histopathological analysis showed that IS induced intestinal inflammation and increased cyclooxygenase-2 (COX-2), nitrotyrosine and Bax expression in intestinal tissue. In IEC-6 cells, IS (125–1000 µM) increased tumor necrosis factor-α levels, COX-2 and inducible nitric oxide synthase expression and nitrotyrosine formation. Moreover, IS increased pro-oxidant, pro-inflammatory and pro-apoptotic parameters in peritoneal macrophages from IS-treated mice. Also, the serum concentration of IS and pro-inflammatory levels of cytokines resulted increased in IS-treated mice. Our results indicate that IS significantly contributes to affect intestinal homeostasis, immune response, and to induce a systemic pro-inflammatory state thus highlighting its potential role as therapeutic target in CKD patients. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease 2.0)

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23 pages, 5383 KiB

Open AccessArticle

Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway

by Wen-Chih Liu, Jia-Fwu Shyu, Yuh-Feng Lin, Hui-Wen Chiu, Paik Seong Lim, Chien-Lin Lu, Cai-Mei Zheng, Yi-Chou Hou, Po-Han Chen and Kuo-Cheng Lu

Int. J. Mol. Sci. 2020, 21(20), 7483; https://doi.org/10.3390/ijms21207483 - 11 Oct 2020

Cited by 24 | Viewed by 3778

Abstract

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR [...] Read more.

Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 μM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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16 pages, 4078 KiB

Open AccessArticle

Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

by Chien-Ning Hsu, Hung-Wei Yang, Chih-Yao Hou, Guo-Ping Chang-Chien, Sufan Lin and You-Lin Tain

Int. J. Mol. Sci. 2020, 21(19), 7237; https://doi.org/10.3390/ijms21197237 - 30 Sep 2020

Cited by 39 | Viewed by 3864

Abstract

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program [...] Read more.

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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17 pages, 4122 KiB

Open AccessArticle

Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

by Wen-Chih Liu, Jia-Fwu Shyu, Paik Seong Lim, Te-Chao Fang, Chien-Lin Lu, Cai-Mei Zheng, Yi-Chou Hou, Chia-Chao Wu, Yuh-Feng Lin and Kuo-Cheng Lu

Int. J. Mol. Sci. 2020, 21(10), 3486; https://doi.org/10.3390/ijms21103486 - 15 May 2020

Cited by 27 | Viewed by 3712

Abstract

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing [...] Read more.

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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19 pages, 3508 KiB

Open AccessArticle

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

by Suvi Törmänen, Päivi Lakkisto, Arttu Eräranta, Peeter Kööbi, Ilkka Tikkanen, Onni Niemelä, Jukka Mustonen and Ilkka Pörsti

Int. J. Mol. Sci. 2020, 21(3), 936; https://doi.org/10.3390/ijms21030936 - 31 Jan 2020

Cited by 1 | Viewed by 3014

Abstract

Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric [...] Read more.

Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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14 pages, 3686 KiB

Open AccessArticle

NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis

by Francesca Bonomini, Mariane Dos Santos, Francisco Veríssimo Veronese and Rita Rezzani

Int. J. Mol. Sci. 2019, 20(14), 3466; https://doi.org/10.3390/ijms20143466 - 15 Jul 2019

Cited by 44 | Viewed by 4715

Abstract

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported [...] Read more.

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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18 pages, 6639 KiB

Open AccessArticle

Effect of Indoxyl Sulfate on the Repair and Intactness of Intestinal Epithelial Cells: Role of Reactive Oxygen Species’ Release

by Simona Adesso, Marco Ruocco, Shara Francesca Rapa, Fabrizio Dal Piaz, Biagio Raffaele Di Iorio, Ada Popolo, Giuseppina Autore, Fuyu Nishijima, Aldo Pinto and Stefania Marzocco

Int. J. Mol. Sci. 2019, 20(9), 2280; https://doi.org/10.3390/ijms20092280 - 8 May 2019

Cited by 40 | Viewed by 4218

Abstract

Chronic kidney disease (CKD) is characterized by an oxidative stress status, driving some CKD-associated complications, even at the gastrointestinal level. Indoxyl Sulfate (IS) is a protein-bound uremic toxin, poorly eliminated by dialysis. This toxin is able to affect the intestinal system, but its [...] Read more.

Chronic kidney disease (CKD) is characterized by an oxidative stress status, driving some CKD-associated complications, even at the gastrointestinal level. Indoxyl Sulfate (IS) is a protein-bound uremic toxin, poorly eliminated by dialysis. This toxin is able to affect the intestinal system, but its molecular mechanism/s in intestinal epithelial cells (IECs) remain poorly understood. This study’s aim was to evaluate the effect of IS (31.2–250 µM) on oxidative stress in IEC-6 cells and on the intactness of IECs monolayers. Our results indicated that IS enhanced oxidative cell damage by inducing reactive oxygen species (ROS) release, reducing the antioxidant response and affecting Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation as well its related antioxidant enzymes. In the wound healing assay model, IS reduced IEC-6 migration, slightly impaired actin cytoskeleton rearrangement; this effect was associated with connexin 43 alteration. Moreover, we reported the effect of CKD patients’ sera in IEC-6 cells. Our results indicated that patient sera induced ROS release in IEC-6 cells directly related to IS sera content and this effect was reduced by AST-120 serum treatment. Results highlighted the effect of IS in inducing oxidative stress in IECs and in impairing the intactness of the IECs cell monolayer, thus significantly contributing to CKD-associated intestinal alterations. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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11 pages, 3054 KiB

Open AccessArticle

Gut Microbiota-Dependent Trimethylamine N-Oxide Pathway Associated with Cardiovascular Risk in Children with Early-Stage Chronic Kidney Disease

by Chien-Ning Hsu, Pei-Chen Lu, Mao-Hung Lo, I-Chun Lin, Guo-Ping Chang-Chien, Sufan Lin and You-Lin Tain

Int. J. Mol. Sci. 2018, 19(12), 3699; https://doi.org/10.3390/ijms19123699 - 22 Nov 2018

Cited by 37 | Viewed by 5031

Abstract

Despite cardiovascular disease (CVD) being the leading cause of morbidity and mortality in chronic kidney disease (CKD), less attention has been paid to subclinical CVD in children and adolescents with early CKD stages. Gut microbiota and their metabolite, trimethylamine N-oxide (TMAO), have [...] Read more.

Despite cardiovascular disease (CVD) being the leading cause of morbidity and mortality in chronic kidney disease (CKD), less attention has been paid to subclinical CVD in children and adolescents with early CKD stages. Gut microbiota and their metabolite, trimethylamine N-oxide (TMAO), have been linked to CVD. Ambulatory blood-pressure monitoring (ABPM) and arterial-stiffness assessment allow for early detection of subclinical CVD. We therefore investigated whether gut microbial composition and TMAO metabolic pathway are correlated with blood-pressure (BP) load and vascular abnormalities in children with early-stage CKD. We enrolled 86 children with G1–G3 CKD stages. Approximately two-thirds of CKD children had BP abnormalities on ABPM. Children with CKD stage G2–G3 had a higher uric acid level (6.6 vs. 4.8 mg/dL, p < 0.05) and pulse-wave velocity (4.1 vs. 3.8 m/s, p < 0.05), but lower TMAO urinary level (209 vs. 344 ng/mg creatinine, p < 0.05) than those with stage G1. Urinary TMAO level was correlated with the abundances of genera Bifidobacterium (r = 0.307, p = 0.004) and Lactobacillus (r = 0.428, p < 0.001). CKD children with abnormal ABPM profile had a lower abundance of the Prevotella genus than those with normal ABPM (p < 0.05). Our results highlight the link between gut microbiota, microbial metabolite TMAO, BP load, and arterial-stiffness indices in children with early-stage CKD. Early assessments of these surrogate markers should aid in decreasing cardiovascular risk in childhood CKD. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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Review

Jump to: Research

16 pages, 2639 KiB

Open AccessReview

Influence of Resveratrol on the Cardiovascular Health Effects of Chronic Kidney Disease

by Jenn-Yeu Song, Ta-Chung Shen, Yi-Chou Hou, Jia-Feng Chang, Chien-Lin Lu, Wen-Chih Liu, Po-Jui Chen, Bo-Hau Chen, Cai-Mei Zheng and Kuo-Cheng Lu

Int. J. Mol. Sci. 2020, 21(17), 6294; https://doi.org/10.3390/ijms21176294 - 31 Aug 2020

Cited by 18 | Viewed by 6108

Abstract

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce [...] Read more.

Cardiovascular disease (CVD) is closely related to chronic kidney disease (CKD), and patients with CKD have a high risk of CVD-related mortality. Traditional CVD risk factors cannot account for the higher cardiovascular risk of patients with CKD, and standard CVD interventions cannot reduce the mortality rates among patients with CKD. Nontraditional factors related to mineral and vitamin-D metabolic disorders provide some explanation for the increased CVD risk. Non-dialyzable toxins, indoxyl sulfate (IS) and p-cresol sulfate (PCS)—produced in the liver by colonic microorganisms—cause kidney and vascular dysfunction. Plasma trimethylamine-N-oxide (TMAO)—a gut microbe-dependent metabolite of dietary L-carnitine and choline—is elevated in CKD and related to vascular disease, resulting in poorer long-term survival. Therefore, the modulation of colonic flora can improve prospects for patients with CKD. Managing metabolic syndrome, anemia, and abnormal mineral metabolism is recommended for the prevention of CVD in patients with CKD. Considering nontraditional risk factors, the use of resveratrol (RSV), a nutraceutical, can be helpful for patients with CVD and CKD. This paper discusses the beneficial effects of RSV on biologic, pathophysiological and clinical responses, including improvements in intestinal epithelial integrity, modulation of the intestinal microbiota and reduction in hepatic synthesis of IS, PCS and TMAO in patients with CVD and CKD. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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13 pages, 1616 KiB

Open AccessReview

Epicardial Adipose Tissue, Adiponectin and Leptin: A Potential Source of Cardiovascular Risk in Chronic Kidney Disease

by Luis D’Marco, Maria Jesús Puchades, Jose Luis Gorriz, Maria Romero-Parra, Marcos Lima-Martínez, Carlos Soto, Valmore Bermúdez and Paolo Raggi

Int. J. Mol. Sci. 2020, 21(3), 978; https://doi.org/10.3390/ijms21030978 - 1 Feb 2020

Cited by 25 | Viewed by 6974

Abstract

The importance of cardiometabolic factors in the inception and progression of atherosclerotic cardiovascular disease is increasingly being recognized. Beyond diabetes mellitus and metabolic syndrome, other factors may be responsible in patients with chronic kidney disease (CKD) for the high prevalence of cardiovascular disease, [...] Read more.

The importance of cardiometabolic factors in the inception and progression of atherosclerotic cardiovascular disease is increasingly being recognized. Beyond diabetes mellitus and metabolic syndrome, other factors may be responsible in patients with chronic kidney disease (CKD) for the high prevalence of cardiovascular disease, which is estimated to be 5- to 20-fold higher than in the general population. Although undefined uremic toxins are often blamed for part of the increased risk, visceral adipose tissue, and in particular epicardial adipose tissue (EAT), have been the focus of intense research in the past two decades. In fact, several lines of evidence suggest their involvement in atherosclerosis development and its complications. EAT may promote atherosclerosis through paracrine and endocrine pathways exerted via the secretion of adipocytokines such as adiponectin and leptin. In this article we review the current knowledge of the impact of EAT on cardiovascular outcomes in the general population and in patients with CKD. Special reference will be made to adiponectin and leptin as possible mediators of the increased cardiovascular risk linked with EAT. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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26 pages, 957 KiB

Open AccessReview

Inflammation and Oxidative Stress in Chronic Kidney Disease—Potential Therapeutic Role of Minerals, Vitamins and Plant-Derived Metabolites

by Shara Francesca Rapa, Biagio Raffaele Di Iorio, Pietro Campiglia, August Heidland and Stefania Marzocco

Int. J. Mol. Sci. 2020, 21(1), 263; https://doi.org/10.3390/ijms21010263 - 30 Dec 2019

Cited by 276 | Viewed by 16879

Abstract

Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation [...] Read more.

Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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9 pages, 338 KiB

Open AccessReview

Management of Diabetes Mellitus in Normal Renal Function, Renal Dysfunction and Renal Transplant Recipients, Focusing on Glucagon-Like Peptide-1 Agonist: A Review Based upon Current Evidence

by Shang-Feng Tsai and Cheng-Hsu Chen

Int. J. Mol. Sci. 2019, 20(13), 3152; https://doi.org/10.3390/ijms20133152 - 28 Jun 2019

Cited by 11 | Viewed by 3942

Abstract

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor [...] Read more.

Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug–drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired β-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be implemented for recipients while closely monitoring their tacrolimus levels and any potential side effects. Any added benefits, in addition to sugar level control, still require more well-designed studies to prove their existence. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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17 pages, 754 KiB

Open AccessReview

Mitochondria as a Source and a Target for Uremic Toxins

by Vasily A. Popkov, Denis N. Silachev, Arthur O. Zalevsky, Dmitry B. Zorov and Egor Y. Plotnikov

Int. J. Mol. Sci. 2019, 20(12), 3094; https://doi.org/10.3390/ijms20123094 - 25 Jun 2019

Cited by 44 | Viewed by 6008

Abstract

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, [...] Read more.

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins. Full article

(This article belongs to the Special Issue Bioactive and Uremic Toxins in Chronic Kidney Disease)

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