Familial hyperkalemic hypertension (FHHt; also called pseudohypoaldosteronism type II) is a hereditary hypertensive disease which can be caused by mutations in four genes:
WNK1
with no lysine (K) 1,
...WNK4
,
Kelch-like3
(KLHL3), and
cullin3
(CUL3). Decreased KLHL3 expression was identified as being involved in the pathogenesis of FHHt caused by cullin 3 disease mutations. Recent studies have revealed an increased WNK4 and hence Na-Cl cotransporter (NCC) activity in the db/db mice, resulting from PKC-mediated KLHL3 phosphorylation, which impairs the degradation of its substrate, WNK4. However, whether WNK4 and NCC were activated in type 1 diabetes still remains unclear. We created streptozotocin-induced type 1 diabetic mice and revealed that renal WNK-oxidative stress response kinase-1/STE20/SPS1-related proline alanine–rich kinase (OSR1/SPAK)-NCC cascade was activated, whereas KLHL3 expression was markedly decreased and CUL3 was heavily neddylated. Moreover, decreased KLHL3 was reversed and WNK1 and WNK4 abundance increased by MLN4924, a neddylation inhibitor. In vitro, our study also showed decreased KLHL3 abundance without any significant change in phosphorylated KLHL3 under high glucose exposure. These results indicate that decreased KLHL3 likely plays a role in the pathogenesis of renal sodium reabsorption in hyperglycemic conditions.
Aims/Introduction
We aimed to evaluate the potential benefits and adverse effects of adding a mineralocorticoid receptor antagonist (MRA) to angiotensin‐converting enzyme inhibitors (ACEI) and/or ...angiotensin receptor blockers (ARB), as standard treatment in patients with diabetic nephropathy.
Materials and Methods
We scanned the Embase, PubMed and Cochrane Central Register of Controlled Trials databases for human clinical trials published in English until June 2016, evaluating renal outcomes in patients with diabetic nephropathy.
Results
A total of 18 randomized controlled trials involving 1,786 patients were included. Compared with ACEI/ARB alone, co‐administration of MRA and ACEI/ARB significantly reduced urinary albumin excretion and the urinary albumin–creatinine ratio (mean difference −69.38, 95% confidence intervals −103.53 to −35.22, P < 0.0001; mean difference −215.74, 95% confidence intervals −409.22 to −22.26, P = 0.03, respectively). A decrease of blood pressure was also found in the co‐administration of MRA and ACEI/ARB groups. However, we did not observe any improvement in the glomerular filtration rate. There was a significant increase in the risk of hyperkalemia on the addition of MRA to ACEI/ARB treatment (relative risk 3.74, 95% confidence intervals 2.30–6.09, P < 0.00001).
Conclusions
These findings suggest that co‐administration of MRA and ACEI/ARB has beneficial effects on renal outcomes with increasing the incidence of hyperkalemia.
The effects of mineralocorticoid receptor antagonists treatment in patients with diabetic nephropathy remain controversial now. Co‐administration of MRA and ACEI/ARB has beneficial effects on renal outcomes with increasing the incidence of hyperkalemia.
Abstract
Background
Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the
GLA
gene. Among more than 1100 reported
...GLA
mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD.
Methods and results
We report a novel hemizygous deep intronic
GLA
mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic
GLA
mutation associated with renal variant of FD, was identified by Sanger sequencing the entire
GLA
genomic DNA sequence of the patient’s peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length
GLA
transcript accounting for about 25% of total
GLA
transcript, along with two major aberrantly spliced
GLA
transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T.
Conclusions
The identification of IVS4+1326C>T establishes a link between deep intronic
GLA
mutation and the renal variant of FD, which extends the mutation spectrum in
GLA
gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic
GLA
mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.
IntroductionHaemodialysis (HD) is the cornerstone treatment for patients with end-stage renal disease (ESRD). However, highly protein bound or large molecular weight uremic toxins such as phenolic ...and indolic compounds and homocysteine, which are associated with adverse outcomes such as cardiovascular disease of patients with ESRD, are difficult to remove via HD but can be effectively eliminates by haemoperfusion (HP). The proposed trial (referred to as HD/HP vs HD below) is a randomised, open-label, multicentre trial comparing HD plus HP versus HD alone in adult patients with ESRD. The primary endpoint measure is all-cause mortality.Methods and analysisWe plan to enrol 1364 maintenance HD patients from 11 medical centres in Shanghai. Participants will be randomised to receive HD plus HP or HD alone at a 1:1 ratio after 1-month run-in period. In both arms, patients will receive low-flux HD at a frequency of two times a week and haemodiafiltration at a frequency of once a week. In the intervention group, subjects also received HP once every 2 weeks. Follow-up is scheduled at 3, 6, 12, 18 and 24 months after randomisation, and will consist the following: routine physical examinations, standard lab panels (blood routine, liver/residual kidney functions, tests of the coagulation system, etc), dialysis adequacy (standard Kt/V), chest X-ray, ECG, echocardiography, heart function rating. Adverse events will be assessed according to the international conference on harmonisation guidelines. The primary outcome is 24-month all-cause mortality. Secondary outcomes will include cardiovascular-related mortality, the occurrence of major cardiovascular events and the quality of life.Ethics and disseminationThe study protocol has been approved by the Ethical Committees of all 11 participating centres. Clinical Research Unit of Xin Hua Hospital will oversee the study. The results will be presented at national and international academic meetings, and submitted to peer-reviewed journals for publications.Trial registration number NCT03227770; Pre-results.
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel ...susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
Skeletal muscle atrophy is an important clinical characteristic of chronic kidney disease (CKD); however, at present, the therapeutic approaches to muscle atrophy induced by CKD are still at an early ...stage of development. Resveratrol is used to attenuate muscle atrophy in other experimental models, but the effects on a CKD model are largely unknown. Here, we showed that resveratrol prevented an increase in MuRF1 expression and attenuated muscle atrophy in vivo model of CKD. We also found that phosphorylation of NF-κB was inhibited at the same time. Dexamethasone-induced MuRF1 upregulation was significantly attenuated in C2C12 myotubes by resveratrol in vitro, but this effect on C2C12 myotubes was abrogated by a knockdown of NF-κB, suggesting that the beneficial effect of resveratrol was NF-κB dependent. Our findings provide novel information about the ability of resveratrol to prevent or treat muscle atrophy induced by CKD.
•The treatment to muscle atrophy induced by CKD is at early stage.•Resveratrol prevents MuRF1 upregulation and attenuates muscle atrophy in CKD.•The protective effects of resveratrol is NF-κB dependent.
Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.
Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a ...replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.
Identification of three novel loci (rs6427389 on 1q23.1
=8.18×10
, OR=1.132, rs6942325 on 6p25.3
=1.62×10
, OR=1.165, and rs2240335 on 1p36.13
=5.10×10
, OR=1.114), implicates
,
, and
as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of
, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on
. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and
showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).
A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
Acute kidney injury (AKI) is a disease where kidney function is lost almost instantaneously; it can develop very rapidly over few hours to maximum of few days. Despite the advent of technology, the ...clinical management against this disease is very poor, and most of the time it is life-threatening. AKI has been actively regulated by extracellular matrix proteins (ECM), however, its underlying mechanism of regulation during AKI progression is very poorly understood. In this study, we explored the integrated network of mRNA and microRNAs (miRNAs) that maintains the progression of ECM after induction of AKI by lethal ischemia. To identify key regulators of ECM, we screened large number of transcriptomes using laser capture microdissection (LCM) technique in addition to microarray and RT-qPCR. Our result clearly showed that 9 miRNAs including miR-21, miR-483, miR-5115, miR-204e, miR-128, miR-181c, miR-203, miR-204 and miR-204c were highly regulated, out of which miR-204 expression change (decrease) was most drastic during ischemia/reperfusion. Detail mechanistic study utilizing combined experimental and computational approach revealed that TGF-β signaling pathway was potentially modulated by deregulated miRNA-204 through SP1, where the TGF-β signaling pathway plays a vital role in ECM regulation. Apart from targeting SP1 and antagonizing epithelial-mesenchymal transition (EMT) signaling our result also showed that miR-204 protects interstitial tissue of renal tubules from chronic fibrotic change. Altogether our study provides sufficient details of how miRNA mediated ECM regulation occur during AKI, which can be effectively utilized in future for better AKI management and diagnosis.
This was the first multicenter, cross-sectional survey to assess the prevalence of anemia, patient awareness, and treatment status in China. Data of patients with chronic kidney disease (CKD; age, ...18-75 years; both out- and inpatients) from 25 hospitals in Shanghai, seeking medical treatment at the nephrology department, were collected between July 1, 2012 and August 31, 2012. The prevalence, awareness, and treatment of anemia in patients with nondialysis CKD (ND-CKD) were assessed. Anemia was defined as serum hemoglobin (Hb) levels ≤12 g/dL in women and ≤13 g/dL in men. A total of 2420 patients with ND-CKD were included. Anemia was established in 1246 (51.5%) patients: 639 (51.3%) men and 607 (48.7%) women. The prevalence of anemia increased with advancing CKD stage (χtrend = 675.14, P < 0.001). Anemia was more prevalent in patients with diabetic nephropathy (68.0%) than in patients with hypertensive renal damage (56.6%) or chronic glomerulonephritis (46.1%, both P < 0.001). Only 39.8% of the anemic patients received treatment with erythropoietin and 27.1% patients received iron products; furthermore, 22.7% of the patients started receiving treatment when their Hb level reached 7 g/dL. The target-achieving rate (Hb at 11-12 g/dL) was only 8.2%. Of the 1246 anemia patients, only 7.5% received more effective and recommended intravenous supplementation. Anemia is highly prevalent in patients with ND-CKD in China, with a low target-achieving rate and poor treatment patterns. The study highlights the need to improve multiple aspects of CKD management to delay the progression of renal failure.
In this investigation, eight novel 2,5-disubstituted 1,2,4-triazolo1,5-apyrimidin-7(4H)-one and eight novel 2,5-disubstituted 1,2,4-triazolo1,5-apyrimidine amine derivatives were synthesized based on ...the novel marine natural product Essramycin. Their anti-epileptic activities were evaluated by 4-aminopyridine (4-AP)-induced hyper excitability model in primary cultured neocortical neurons. Five compounds with 1,2,4-triazolo1,5-apyrimidin-7(4H)-one skeleton showed remarkable anti-epileptic activities. The preliminary structure-activity relationship (SAR) showed that the pyrimidine-7(4H)-one motif is the necessary "active core" of anti-epileptic activity. To understand the action mechanism of anti-epileptic activity of 1,2,4-triazolo1,5-apyrimidin-7(4H)-one compounds, docking studies using the model of GABA
A
as docking scaffolds were performed and the docking results were in concordance with the experiment observations.
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