Alkaline phosphatase: a novel treatment target for cardiovascular disease in CKD
TL;DR: Novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases are reviewed and new drugs that target ALP are discussed, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.
Abstract: Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role Four genes encode ALP isozymes in humans Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney TNALP has a pivotal role in bone calcification Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization
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TL;DR: In this article, the potential of epigenetic therapeutic strategies against bromodomain and extraterminal (BET) proteins for CKD treatment and associated risks is discussed.
Abstract: Epigenetic mechanisms, especially DNA methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. The bromodomain and extraterminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. Experimental data have demonstrated the involvement of some BET proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. Selective bromodomain inhibitors are epigenetic drugs that block the interaction between BET proteins and acetylated proteins, thus exerting beneficial effects. Recent data have described the beneficial effect of BET inhibition on experimental renal diseases. Emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (CKD). Several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in CKD patients. Here, we review how targeting bromodomains in BET proteins may regulate essential processes involved in renal diseases and in associated complications found in CKD patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against BET proteins for CKD treatment and associated risks.
63 citations
Cites background from "Alkaline phosphatase: a novel treat..."
...There are previous references about the role of ALP with adverse cardiovascular outcomes in CKD patients that normally developed vascular calcification (Haarhaus et al., 2017) (Taliercio et al., 2013)....
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...There are previous references about the role of ALP with adverse cardiovascular outcomes in CKD patients that normally developed vascular calcification (Haarhaus et al., 2017) (Taliercio et al....
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TL;DR: This study constructed the first fluorescent probe (TPEPy-pY) for sensing bacterial ALP activity and shows excellent selectivity and sensitivity for ALP activity, and envision that more self-assembling fluorescent probes will be designed with higher sensitivity in the near future.
Abstract: Abnormal levels of alkaline phosphatase (ALP) activity are associated with various diseases, and many ALP probes have been developed to date. However, the development of ALP-sensitive probes for living cells, especially for the detection of bacterial ALP, remains challenging because of the complex and dynamic context. In this study, we constructed the first fluorescent probe (TPEPy-pY) for sensing bacterial ALP activity. TPEPy-pY is an AIEgen-peptide conjugate with property of aggregation-induced emission (AIE) and could turn on its fluorescence by ALP-catalyzed in situ self-assembly of the probe. The probe shows excellent selectivity and sensitivity for ALP activity, with a detection limit of 6.6 × 10-3 U mL-1. TPEPy-pY performs well in detection and in situ imaging of bacterial ALP activity against E. coli. Also, the detection does not require tedious washing steps and takes approximately 1 h, which is advantageous over commercial ALP kits. Therefore, the proposed strategy paved a new avenue for bacterial ALP detection, and we envision that more self-assembling fluorescent probes will be designed with higher sensitivity in the near future.
58 citations
TL;DR: This guideline on the management of patients with diabetes and CKD stage 3b or higher to facilitate informed decision-making by health care professionals with focus on selection of renal replacement therapy, management of glycemic control, and management and prevention of cardiovascular risk is published.
57 citations
TL;DR: Nearly all data confirm the potent anti-inflammatory properties of (I)AP and the negative consequences of its inhibition on health, thus emphasizing nutrition as a potent lever for limiting inflammation.
Abstract: In recent years, much new data on intestinal alkaline phosphatase (IAP) have been published, and major breakthroughs have been disclosed. The aim of the present review is to critically analyze the publications released over the last 5 years. These breakthroughs include, for example, the direct implication of IAP in intestinal tight junction integrity and barrier function maintenance; chronic intestinal challenge with low concentrations of Salmonella generating long-lasting depletion of IAP and increased susceptibility to inflammation; the suggestion that genetic mutations in the IAP gene in humans contribute to some forms of chronic inflammatory diseases and loss of functional IAP along the gut and in stools; stool IAP as an early biomarker of incipient diabetes in humans; and omega-3 fatty acids as direct inducers of IAP in intestinal tissue. Many recent papers have also explored the prophylactic and therapeutic potential of IAP and other alkaline phosphatase (AP) isoforms in various experimental settings and diseases. Remarkably, nearly all data confirm the potent anti-inflammatory properties of (I)AP and the negative consequences of its inhibition on health. A simplified model of the body AP system integrating the IAP compartment is provided. Finally, the list of nutrients and food components stimulating IAP has continued to grow, thus emphasizing nutrition as a potent lever for limiting inflammation.
54 citations
TL;DR: In this paper, the authors provided direct evidence for the molecular basis of this futile creatine cycling activity in mice, which was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed.
Abstract: Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1-3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle.
49 citations
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TL;DR: This study’s findings can provide practical guidelines to steer partnership programs within the academic and clinical bodies, with the aim of providing a collaborative partnership approach to clinical education.
Abstract: The aim of our systematic review was to retrieve and integrate relevant evidence related to the process of formation and implementation of the academic–service partnership, with the aim of reformin...
41,134 citations
TL;DR: In this review the usual methods applied in systematic reviews and meta-analyses are outlined, and the most common procedures for combining studies with binary outcomes are described, illustrating how they can be done using Stata commands.
31,656 citations
TL;DR: The longitudinal glomerular filtration rate was estimated among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation.
Abstract: Background End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. Methods We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. Results The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1....
9,642 citations
TL;DR: In this paper, the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation.
Abstract: Background End-stage renal disease substantially increases the risks of death, cardiovascular disease, and use of specialized health care, but the effects of less severe kidney dysfunction on these outcomes are less well defined. Methods We estimated the longitudinal glomerular filtration rate (GFR) among 1,120,295 adults within a large, integrated system of health care delivery in whom serum creatinine had been measured between 1996 and 2000 and who had not undergone dialysis or kidney transplantation. We examined the multivariable association between the estimated GFR and the risks of death, cardiovascular events, and hospitalization. Results The median follow-up was 2.84 years, the mean age was 52 years, and 55 percent of the group were women. After adjustment, the risk of death increased as the GFR decreased below 60 ml per minute per 1.73 m2 of body-surface area: the adjusted hazard ratio for death was 1.2 with an estimated GFR of 45 to 59 ml per minute per 1.73 m2 (95 percent confidence interval, 1....
2,843 citations
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