Nicotinamide adenine dinucleotide (oxidized form, NAD
) is a critical coenzyme, with functions ranging from redox reactions and energy metabolism in mitochondrial respiration and oxidative ...phosphorylation to being a central player in multiple cellular signaling pathways, organ resilience, health, and longevity. Many of its cellular functions are executed via serving as a co-substrate for sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), and CD38. Kidney damage and diseases are common in the general population, especially in elderly persons and diabetic patients. While NAD
is reduced in acute kidney injury (AKI) and chronic kidney disease (CKD), mounting evidence indicates that NAD
augmentation is beneficial to AKI, although conflicting results exist for cases of CKD. Here, we review recent progress in the field of NAD
, mainly focusing on compromised NAD
levels in AKI and its effect on essential cellular pathways, such as mitochondrial dysfunction, compromised autophagy, and low expression of the aging biomarker αKlotho (Klotho) in the kidney. We also review the compromised NAD
levels in renal fibrosis and senescence cells in the case of CKD. As there is an urgent need for more effective treatments for patients with injured kidneys, further studies on NAD
in relation to AKI/CKD may shed light on novel therapeutics.
Uremic vascular calcification is a regulated cell-mediated process wherein cells in the arterial wall transdifferentiate to actively calcifying cells resulting in a process resembling bone formation. ...Wnt signalling is established as a major driver for vessel formation and maturation and for embryonic bone formation, and disturbed Wnt signalling might play a role in vascular calcification. ICG-001 is a small molecule Wnt inhibitor that specifically targets the coactivator CREB binding protein (CBP)/β-catenin-mediated signalling. In the present investigation we examined the effect of ICG-001 on vascular calcification in uremic rats. Uremic vascular calcification was induced in adult male rats by 5/6-nephrectomy, high phosphate diet and alfacalcidol. The presence of uremic vascular calcification in the aorta was associated with induction of gene expression of the Wnt target gene and marker of proliferation, cyclinD1; the mediator of canonical Wnt signalling, β-catenin and the matricellular proteins, fibronectin and periostin. Furthermore, genes from fibrosis-related pathways, TGF-β and activin A, as well as factors related to epithelial-mesenchymal transition, snail1 and vimentin were induced. ICG-001 treatment had significant effects on gene expression in kidney and aorta from healthy rats. These effects were however limited in uremic rats, and treatment with ICG-001 did not reduce the Ca-content of the uremic vasculature.
Hyperphosphatemia and vascular calcification are frequent complications of chronic renal failure and bone morphogenetic protein 7 (BMP7) has been shown to protect against development of vascular ...calcification in uremia. The present investigation examined the potential reversibility of established uremic vascular calcification by treatment of uremic rats with BMP7. A control model of isogenic transplantation of a calcified aorta from uremic rats into healthy littermates examined whether normalization of the uremic environment reversed vascular calcification. Uremia and vascular calcification were induced in rats by 5/6 nephrectomy, high phosphate diet and alfacalcidol treatment. After 14 weeks severe vascular calcification was present and rats were allocated to BMP7, vehicle or aorta transplantation. BMP7 treatment caused a significant decrease of plasma phosphate to 1.56 ± 0.17 mmol/L vs 2.06 ± 0.34 mmol/L in the vehicle group even in the setting of uremia and high phosphate diet. Uremia and alfacalcidol resulted in an increase in aortic expression of genes related to fibrosis, osteogenic transformation and extracellular matrix calcification, and the BMP7 treatment resulted in a decrease in the expression of profibrotic genes. The total Ca-content of the aorta was however unchanged both in the abdominal aorta: 1.9 ± 0.6 μg/mg tissue in the vehicle group vs 2.2 ± 0.6 μg/mg tissue in the BMP7 group and in the thoracic aorta: 71 ± 27 μg/mg tissue in the vehicle group vs 54 ± 18 μg/mg tissue in the BMP7 group. Likewise, normalization of the uremic environment by aorta transplantation had no effect on the Ca-content of the calcified aorta: 16.3 ± 0.6 μg/mg tissue pre-transplantation vs 15.9 ± 2.3 μg/mg tissue post-transplantation. Aortic expression of genes directly linked to extracellular matrix calcification was not affected by BMP7 treatment, which hypothetically might explain persistent high Ca-content in established vascular calcification. The present results highlight the importance of preventing the development of vascular calcification in chronic kidney disease. Once established, vascular calcification persists even in the setting when hyperphosphatemia or the uremic milieu is abolished.
IntroductionDiabetic kidney disease is a severe complication of diabetes. The diagnosis is based on clinical characteristics such as persistently elevated albuminuria, hypertension and decline in ...kidney function, although this definition is not specific to kidney disease caused by diabetes. The only way to establish an accurate diagnosis—diabetic nephropathy—is by performing a kidney biopsy. The histological presentation of diabetic nephropathy can be associated with a heterogeneous range of histological features with many pathophysiological factors involved demonstrating the complexity of the condition. Current treatment strategies aim to slow disease progression and are not specific to the underlying pathological processes.This study will investigate the prevalence of diabetic nephropathy in individuals with type 2 diabetes (T2D) and severely elevated albuminuria. The deep molecular characterisation of the kidney biopsy and biological specimens may pave the way for improved diagnostic accuracy and a better understanding of the pathological processes involved and may also reveal new targets for individualised treatment.Methods and analysisIn the PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy 2 study, research kidney biopsies will be performed in 300 participants with T2D, urine albumin/creatinine ratio ≥700 mg/g and estimated glomerular filtration ratio >30 mL/min/1.73 m2. Cutting-edge molecular technologies will be applied to the kidney, blood, urine, faeces and saliva samples for comprehensive multi-omics profiling. The associated disease course and clinical outcomes will be assessed by annual follow-up for 20 years.Ethics and disseminationThe Danish Regional Committee on Health Research Ethics and the Knowledge Center on Data Protection (in the Capital Region of Denmark) have granted approval for the study. The results will be published in peer-reviewed journals.Trial registration numberNCT04916132.
Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world’s population infected with
Mycobacterium tuberculosis
(
M. tuberculosis
) in an asymptomatic latent state ...of which 5–10% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including
M. tuberculosis
. Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin D-mediated antimicrobial activity against
M. tuberculosis
is dependent on the induction of cathelicidin. However, unraveling the immunoregulatory effects of vitamin D in humans is hampered by the lack of suitable experimental models. We have previously described a family in which members suffer from hereditary vitamin D-resistant rickets (HVDRR). The family carry a mutation in the DNA-binding domain of the vitamin D receptor (VDR). This mutation leads to a non-functional VDR, meaning that vitamin D cannot exert its effect in family members homozygous for the mutation. Studies of HVDRR patients open unique possibilities to gain insight in the immunoregulatory roles of vitamin D in humans. Here we describe the impaired ability of macrophages to produce cathelicidin in a HVDRR patient, who in her adolescence suffered from extrapulmonary TB. The present case is a rare experiment of nature, which illustrates the importance of vitamin D in the pathophysiology of combating
M. tuberculosis
.
The active form of vitamin D, 1,25-dihydroxyvitamin D
3
(1,25(OH)
2
D
3
), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in ...the DNA-binding domain of the VDR and its consequences for 1,25(OH)
2
D
3
signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)
2
D
3
and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)
2
D
3
-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)
2
D
3
responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)
2
D
3
-induced translocation of the VDR to the nucleus and 1,25(OH)
2
D
3
-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.
The Dancing Nurses and the Language of the Body Winther, Helle; Grøntved, Susanne Næsgaard; Kold Gravesen, Eva ...
Journal of holistic nursing,
09/2015, Letnik:
33, Številka:
3
Journal Article
Recenzirano
At first glance, dance and movement may appear foreign to the idea of nurse education. On closer inspection, it could be high time. The flow of words may stop, but the body is always in ...movement—always communicating. Still, the language of the body, and certainly movement, is an often overlooked potential in education. This is also true for nurse education: in spite of the often bodily close meetings with vulnerable and crisis-stricken patients. These meetings make great demands on the nurse to both contain own feelings and be able to “read” and understand patients’ often only sense-based communication. This dimension of the nursing profession can be overwhelming, touching, and shocking for young nursing students. This research project examines, whether a course composed of theory, dance and movement lessons, and increased focus on the bodily communication between students and patients may be developmental for the nursing students’ beginning embodied professionality. Results from the project have innovative educational potentials. They also give concrete indications of how nursing educations can develop new holistic anchored embodied training in a very accessible, as well as essential, ancient, and unavoidably present part of the nursing profession.
Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is ...normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we examined changes in methylation levels of parathyroid CaR and VDR promoters in vivo and in vitro. Methods. Uremia was induced by 5/6 nephrectomy. Melting temperature profiling of CaR and VDR PCR products after bisulfite treatment of genomic DNA from rat parathyroids was performed. Real-time PCR measured expression of PTH, CaR, VDR, and klotho genes in vitro. Results. Parathyroids from uremic rats had similar low levels of methylation in vivo and in vitro. In culture, a significant downregulation of CaR, VDR, and klotho within two hours of incubation was observed, while housekeeping genes remained stable for 24 hours. Conclusion. In uremic s-HPT and in vitro, no overall changes in methylation levels in the promoter regions of parathyroid CaR and VDR genes were found. Thus, epigenetic methylation of these promoters does not explain decreased parathyroid expression of CaR and VDR genes in uremic s-HPT.
High circulating levels of fibroblast growth factor 23 (FGF23) have been demonstrated in kidney failure, but mechanisms of this are not well understood. Here we examined the impact of the kidney on ...the early regulation of intact FGF23 in acute uremia as induced by bilateral or unilateral nephrectomy (BNX and UNX, respectively) in the rat. BNX induced a significant increase in plasma intact FGF23 levels from 112 to 267pg/ml within 15min, which remained stable thereafter. UNX generated intact FGF23 levels between that seen in BNX and sham-operated rats. The intact to C-terminal FGF23 ratio was significantly increased in BNX rats. The rapid rise in FGF23 after BNX was independent of parathyroid hormone or FGF receptor signaling. No evidence of early stimulation of FGF23 gene expression in the bone was found. Furthermore, acute severe hyperphosphatemia or hypercalcemia had no impact on intact FGF23 levels in normal and BNX rats. The half-life of exogenous recombinant human FGF23 was significantly prolonged from 4.4 to 11.8min in BNX rats. Measurements of plasma FGF23 in the renal artery and renal vein demonstrated a significant renal extraction. Thus the kidney is important in FGF23 homeostasis by regulation of its plasma level and metabolism.
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