Lipid accumulation in renal cells has been implicated in the pathogenesis of obesity-related kidney disease, and lipotoxicity in the kidney can be a surrogate marker for renal failure or renal ...fibrosis. Fatty acid oxidation provides energy to renal tubular cells. Ca
is required for mitochondrial ATP production and to decrease reactive oxygen species (ROS). However, how nifedipine (a calcium channel blocker) affects lipogenesis is unknown. We utilized rat NRK52E cells pre-treated with varying concentrations of nifedipine to examine the activity of lipogenesis enzymes and lipotoxicity. A positive control exposed to oleic acid was used for comparison. Nifedipine was found to activate acetyl Coenzyme A (CoA) synthetase, acetyl CoA carboxylase, long chain fatty acyl CoA elongase, ATP-citrate lyase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase, suggesting elevated production of cholesterol and phospholipids. Nifedipine exposure induced a vast accumulation of cytosolic free fatty acids (FFA) and stimulated the production of reactive oxygen species, upregulated CD36 and KIM-1 (kidney injury molecule-1) expression, inhibited p-AMPK activity, and triggered the expression of SREBP-1/2 and lipin-1, underscoring the potential of nifedipine to induce lipotoxicity with renal damage. To our knowledge, this is the first report demonstrating nifedipine-induced lipid accumulation in the kidney.
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With rapid industrialization, humans produce an increasing number of products. The composition of these products is usually decomposed. However, some substances are not easily broken down and ...gradually become environmental pollutants. In addition, these substances may cause bioaccumulation, since the substances can be fragmented into micro- and nanoparticles. These particles or their interactions with other toxic matter circulate in humans via the food chain or air. Whether these micro- and nanoparticles interfere with extracellular vesicles (EVs) due to their similar sizes is unclear. Micro- and nanoparticles (MSs and NSs) induce several cell responses and are engulfed by cells depending on their size, for example, particulate matter with a diameter ≤2.5 μm (PM2.5). Autophagy is a mechanism by which pathogens are destroyed in cells. Some artificial materials are not easily decomposed in organisms. How do these cells or tissues respond? In addition, autophagy operates through two pathways (increasing cell death or cell survival) in tumorigenesis. Many MSs and NSs have been found that induce autophagy in various cells and tissues. As a result, this review focuses on how these particles interfere with cells and tissues. Here, we review MSs, NSs, and PM2.5, which result in different autophagy-related responses in various tissues or cells.
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Heavy metals causing chronic nephrotoxicity may play a key role in the pathogenesis of chronic kidney disease (CKD). This study hypothesized that plasma folate and vitamin B12 would modify the ...association of CKD with total urinary arsenic and blood lead and cadmium levels. We recruited 220 patients with CKD who had an estimated glomerular filtration rate of <60 mL/min/1.73 m2 for ≥3 consecutive months and 438 sex- and age-matched controls. We performed inductively coupled plasma mass spectrometry to measure blood cadmium and lead levels. The urinary arsenic level was determined using a high-performance liquid chromatography–hydride generator–atomic absorption spectrometry. Plasma vitamin B12 and folate levels were measured through the SimulTRAC-SNB radioassay. Compared with patients with plasma vitamin B12 ≤ 6.27 pg/mL, the odds ratio (OR) and 95% confidence interval of CKD for patients with plasma vitamin B12 > 9.54 pg/mL was 2.02 (1.15–3.55). However, no association was observed between plasma folate concentration and CKD. A high level of plasma vitamin B12 combined with high levels of blood lead and cadmium level and total urinary arsenic tended to increase the OR of CKD in a dose-response manner, but the interactions were nonsignificant. This is the first study to demonstrate that patients with high plasma vitamin B12 level exhibit increased OR of CKD related to high levels of blood cadmium and lead and total urinary arsenic.
Identifying modifiable risk factors of peritoneal dialysis (PD)-related peritonitis is of clinical importance in patient care. Mineral bone disease (MBD) has been associated with mortality and ...morbidity in end-stage kidney disease (ESKD) patients. However, its influence on PD related peritonitis due to altered host immunity remains elusive. This study investigated whether abnormal biomarkers of MBD are associated with the development of peritonitis in patients undergoing maintenance PD. We conducted a retrospective observational cohort study, analysing data derived from a nationwide dialysis registry database in Taiwan, from 2005 to 2012. A total of 5750 ESKD patients commencing PD therapy during this period were enrolled and followed up to 60 months or by the end of the study period. The patients were stratified based on their baseline serum parathyroid hormone (PTH) levels, calcium (Ca) levels or phosphorus (P) levels, respectively or in combinations. The primary outcome was the occurrence of first episode of peritonitis, and patient outcomes such as deaths, transfer to haemodialysis or receiving renal transplantation were censored. Peritonitis-free survival and the influence of PTH, Ca, P (individual or in combination) on the peritonitis occurrence were analysed. A total of 5750 PD patients was enrolled. Of them, 1611 patients experienced their first episode of peritonitis during the study period. Patients with low PTH, high Ca or low P levels, respectively or in combination, had the lowest peritonitis-free survival. After adjusting for age, sex and serum albumin levels, we found that the combinations of low PTH levels with either high Ca levels or low/normal P levels were significant risk factors of developing peritonitis. Abnormal mineral bone metabolism in maintenance PD patients with low serum PTH levels, in combination with either high Ca levels or low/normal P levels, could be novel risk factors of PD-related peritonitis.
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Patients with acute kidney injury (AKI) who survive the acute stage are at notable risk for chronic kidney disease (CKD) progression. There is no single therapy that can effectively prevent the AKI ...to CKD transition. Autophagy is a cytoplasmic component degradation pathway and has complex functions in several diseases, such as renal fibrosis. Previous research has shown that lactoferrin has important functions in antioxidant defense and other defense systems, protecting kidneys against various injuries. The present study investigated the effect of lactoferrin in protecting against the AKI to CKD transition. We identified 62 consensus genes with two-fold changes in clinical kidney tissues from AKI and CKD patients. Among the 62 overlay genes, the mRNA levels of LTF were significantly upregulated in the kidney tissues of AKI and CKD patients. Lactoferrin induced autophagy via the activation of the AMPK and inhibition of Akt/mTOR pathway in human kidney proximal tubular cells. Lactoferrin suppressed oxidative stress-induced cell death and apoptosis by augmenting autophagy. Lactoferrin has an antifibrotic role in human kidney tubular cells. In a mouse model of folic acid-induced AKI to CKD transition, treatment with lactoferrin recovered renal function and further suppressed renal fibrosis through the inhibition of apoptosis and the induction of autophagy. These findings identify lactoferrin as a potential therapeutic target for the prevention of the AKI to CKD transition.
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Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at ...evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia.
Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects.
Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment.
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Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by ...inhibiting the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague-Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups (
< 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys (
< 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.
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We used resveratrol (Res)-loaded nanoparticles (Res NPs) as a novel method for improving the pharmacokinetic properties of Res and analyzed the effect of Res NPs in chronic kidney disease (CKD).
We ...coupled anti-kidney injury molecule-1 antibodies to Res NPs and analyzed safety and efficacy.
Res NPs had low toxicity and induced autophagy. Res NPs inhibited the NLRP3 inflammasome and IL-1β secretion. Higher NLRP3 expression levels were observed in peripheral blood monocytic cells of CKD patients than healthy individuals. Treatment with kidney injury molecule-1-Res NPs significantly reduced creatinine and protected against tubulointerstitial injury in a murine model of CKD.
Res NPs through NLRP3 inflammasome attenuation and autophagy induction may be as a strategy to prevent CKD.
The B-lymphocyte-activating factor (BAFF) is associated with B-cell functions, and gene polymorphisms of the BAFF have been linked to autoimmune diseases (AIDs). In this study, we explored possible ...associations of two BAFF single-nucleotide polymorphisms (SNPs), rs1041569 and rs2893321, with autoimmune thyroid diseases (AITDs) in an ethnic Chinese population.
In total, 319 Graves' disease (GD), 83 Hashimoto's thyroiditis (HT) patients, and 369 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism and direct sequencing were used to genotype rs2893321 and rs1041569.
There was a significant difference in frequencies of the G allele and AG+GG genotype of rs2893321 between the GD and control groups (p = 0.013, odds ratio (OR) = 0.76, and p = 0.017, OR = 0.68, respectively) and between the AITD and control groups (p = 0.009, OR = 0.76, and, p = 0.014, OR = 0.69, respectively). The AA genotype of rs2893321 was associated with low titers of the thyroid-stimulating hormone receptor antibody (TSHRAb) (p = 0.015) in males but not in females. The AA genotype of rs2893321 was associated with the presence of two different types of thyroid autoantibody (TAb) (TSHRAb and Hashimoto's autoantibody (anti-thyroglobulin or anti-microsomal antibody)) in females and with that of one type in males.
rs2893321 may be a susceptible genetic variant for the development of GD and AITDs. Associations of rs2893321 with susceptibility to GD and AITDs and the correlation between rs2893321 and TAb exhibit a dimorphic pattern. Additional studies with larger sample sizes are required to confirm our findings.
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