Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular ...cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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
-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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Vitamin D has been described as an essential nutrient and hormone, which can cause nuclear, non-genomic, and mitochondrial effects. Vitamin D not only controls the transcription of thousands of ...genes, directly or indirectly through the modulation of calcium fluxes, but it also influences the cell metabolism and maintenance specific nuclear programs. Given its broad spectrum of activity and multiple molecular targets, a deficiency of vitamin D can be involved in many pathologies. Vitamin D deficiency also influences mortality and multiple outcomes in chronic kidney disease (CKD). Active and native vitamin D serum levels are also decreased in critically ill patients and are associated with acute kidney injury (AKI) and in-hospital mortality. In addition to regulating calcium and phosphate homeostasis, vitamin D-related mechanisms regulate adaptive and innate immunity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have a role in excessive proinflammatory cell recruitment and cytokine release, which contribute to alveolar and full-body endothelial damage. AKI is one of the most common extrapulmonary manifestations of severe coronavirus disease 2019 (COVID-19). There are also some correlations between the vitamin D level and COVID-19 severity via several pathways. Proper vitamin D supplementation may be an attractive therapeutic strategy for AKI and has the benefits of low cost and low risk of toxicity and side effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal ...system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. ...There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin–angiotensin–aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated ...by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.
The accumulation of the uremic toxin indoxyl sulfate (IS) induces target organ damage in chronic kidney disease (CKD) patients, and causes complications including cardiovascular diseases, renal ...osteodystrophy, muscle wasting, and anemia. IS stimulates reactive oxygen species (ROS) production in CKD, which impairs glomerular filtration by a direct cytotoxic effect on the mesangial cells. IS further reduces antioxidant capacity in renal proximal tubular cells and contributes to tubulointerstitial injury. IS-induced ROS formation triggers the switching of vascular smooth muscular cells to the osteoblastic phenotype, which induces cardiovascular risk. Low-turnover bone disease seen in early CKD relies on the inhibitory effects of IS on osteoblast viability and differentiation, and osteoblastic signaling via the parathyroid hormone. Excessive ROS and inflammatory cytokine releases caused by IS directly inhibit myocyte growth in muscle wasting via myokines’ effects. Moreover, IS triggers eryptosis via ROS-mediated oxidative stress, and elevates hepcidin levels in order to prevent iron flux in circulation in renal anemia. Thus, IS-induced oxidative stress underlies the mechanisms in CKD-related complications. This review summarizes the underlying mechanisms of how IS mediates oxidative stress in the pathogenesis of CKD’s complications. Furthermore, we also discuss the potential role of oral AST-120 in attenuating IS-mediated oxidative stress after gastrointestinal adsorption of the IS precursor indole.
Osteoporosis is a systemic skeletal disorder characterized by a decrease in bone mass and microarchitectural deterioration of bone tissue. The World Health Organization has defined osteoporosis as a ...decrease in bone mass (50%) and bony quality (50%). Vitamin D, a steroid hormone, is crucial for skeletal health and in mineral metabolism. Its direct action on osteoblasts and osteoclasts and interaction with nonskeletal tissues help in maintaining a balance between bone turnover and bone growth. Vitamin D affects the activity of osteoblasts, osteoclasts, and osteocytes, suggesting that it affects bone formation, bone resorption, and bone quality. At physiological concentrations, active vitamin D maintains a normal rate of bone resorption and formation through the RANKL/OPG signal. However, active vitamin D at pharmacological concentration inhibits bone resorption at a higher rate than that of bone formation, which influences the bone quality and quantity. Nutritional vitamin D rather than active vitamin D activates osteoblasts and maintains serum 25(OH)D3 concentration. Despite many unanswered questions, much data support nutritional vitamin D use in osteoporosis patients. This article emphasizes the role of nutritional vitamin D replacement in different turnover status (high or low bone turnover disorders) of osteoporosis together with either anti-resorptive (Bisphosphonate, Denosumab et.) or anabolic (Teriparatide) agents when osteoporosis persists.
•Osteoporosis is composed by quality and quantity of bone mass.•Treatment for osteoporosis should be focused on the bone turnover rate in order to normalize the bone remodeling.•Nutritional vitamin D is an important regulator to maintain the bone remodeling due to its pleotropic effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can ...significantly predict ESRD-associated cognitive decline.
This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI.
In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-β (Aβ)1 - 42, serum indoxyl sulfate, and hematologic and biochemical parameters were measured.
Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aβ1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aβ1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aβ1 - 42 over albumin was 0.785 and significant (p < 0.05).
This cohort study has shown that the ratio of plasma Aβ1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline.
The downregulation of melatonin receptor 1A (MTNR1A) is associated with a range of pathological conditions, including membranous nephropathy. Knowledge of the mechanism underlying MTNR1A expression ...has been limited to the transcriptional regulation level. Here, RNA interference screening in human kidney cells revealed that heterogeneous nuclear ribonucleoprotein L (hnRNPL) upregulated MTNR1A RNA post‐transcriptionally. hnRNPL knockdown or overexpression led to increased or decreased levels of cyclic adenosine monophosphate‐responsive element‐binding protein phosphorylation, respectively. Molecular studies showed that cytoplasmic hnRNPL exerts a stabilizing effect on the MTNR1A transcript through CA‐repeat elements in its coding region. Further studies revealed that the interaction between hnRNPL and MTNR1A serves to protect MNTR1A RNA degradation by the exosome component 10 protein. MTNR1A, but not hnRNPL, displays a diurnal rhythm in mouse kidneys. Enhanced levels of MTNR1A recorded at midnight correlated with robust binding activity between cytoplasmic hnRNPL and the MTNR1A transcript. Both hnRNPL and MTNR1A were decreased in the cytoplasm of tubular epithelial cells from experimental membranous nephropathy kidneys, supporting their clinical relevance. Collectively, our data identified cytoplasmic hnRNPL as a novel player in the upregulation of MTNR1A expression in renal tubular epithelial cells, and as a potential therapeutic target.
Our results suggest that the diurnal rhythmic variation in melatonin receptor 1A (MTNR1A) levels may depend on binding to heterogeneous nuclear ribonucleoprotein L (hnRNPL) in the cytoplasm. Both hnRNPL and MTNR1A were downregulated in the cytoplasm of renal tubular epithelial cells from experimental membranous nephropathy kidneys. Our results provide a positive oscillatory mechanism between the cytoplasmic hnRNPL protein and the MTNR1A messenger RNA for the modulation of this pathological condition.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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