28 research outputs found
Pre-Interventional Kynurenine Predicts Medium-Term Outcome after Contrast Media Exposure Due to Coronary Angiography
Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a
serious complication of contrast media enhanced procedures like coronary
angiography. There is still a lack of established biomarkers that help to
identify patients at high risk for short and long-term complications. The aim
of the current study was to evaluate plasma kynurenine as a predictive
biomarker for CI-AKI and long-term complications, measured by the combined
endpoint "major adverse kidney events" (MAKE) up to 120 days after CM
application. Methods: In this prospective cohort study 245 patients undergoing
coronary angiography were analyzed. Blood samples were obtained at baseline,
24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients
were followed for 120 days for adverse clinical events including death, the
need for dialysis, and a doubling of plasma creatinine. Occurrence of any of
these events was summarized in the combined endpoint MAKE. Results:
Preinterventional plasma kynurenine was not associated with CI-AKI. Patients
who later developed MAKE displayed significantly increased preinterventional
plasma kynurenine levels (p<0.0001). ROC analysis revealed that
preinterventional kynurenine is highly predictive for MAKE (AUC=0.838;
p<0.0001). The optimal cutoff was found at ≥3.5 µmol/L Using this cutoff, the
Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine
≥3.5 µmol/L were significantly associated with a higher prevalence of MAKE
until follow up (p<0.0001). This association remained significant in
multivariate Cox regression models adjusted for relevant factors of long-term
renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as
a highly predictive biomarker for MAKE up to 120 days after coronary
angiography
Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography
Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein
that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex.
In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule
epithelial cells reducing the urinary excretion to trace amounts. Acute
tubular injury is expected to result in urinary VDBP loss. The purpose of our
study was to explore the potential role of urinary VDBP as a biomarker of an
acute renal damage. Method We included 314 patients with diabetes mellitus or
mild renal impairment undergoing coronary angiography and collected blood and
urine before and 24 hours after the CM application. Patients were followed for
90 days for the composite endpoint major adverse renal events (MARE: need for
dialysis, doubling of serum creatinine after 90 days, unplanned emergency
rehospitalization or death). Results Increased urine VDBP concentration 24
hours after contrast media exposure was predictive for dialysis need (no
dialysis: 113.06 ± 299.61ng/ml, n = 303; need for dialysis: 613.07 ± 700.45
ng/ml, n = 11, Mean ± SD, p<0.001), death (no death during follow-up: 121.41 ±
324.45 ng/ml, n = 306; death during follow-up: 522.01 ± 521.86 ng/ml, n = 8;
Mean ± SD, p<0.003) and MARE (no MARE: 112.08 ± 302.00ng/ml, n = 298; MARE:
506.16 ± 624.61 ng/ml, n = 16, Mean ± SD, p<0.001) during the follow-up of 90
days after contrast media exposure. Correction of urine VDBP concentrations
for creatinine excretion confirmed its predictive value and was consistent
with increased levels of urinary Kidney Injury Molecule-1 (KIM-1) and baseline
plasma creatinine in patients with above mentioned complications. The impact
of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors
such as anemia, preexisting renal failure, preexisting heart failure, and
diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major
contrast induced nephropathy-associated events 90 days after contrast media
exposure
Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone
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Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
ABSTRACT Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood
Renale Effekte des Dipeptidylpeptidase-Inhibitors Linagliptin in nicht- diabetischen Ratten mit 5/6 Nephrektomie
Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD)
progression in experimental diabetic nephropathy in a glucose-independent
manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus
telmisartan in preventing CKD progression in non-diabetic rats with 5/6
nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus
placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and
5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly
decreased by 48% with linagliptin but a non-significant 24% with telmisartan
versus placebo. The urine albumin-to-creatinine ratio was significantly
decreased by 66% with linagliptin and 92% with telmisartan versus placebo.
Blood pressure was significantly lowered by telmisartan, but it was not
affected by linagliptin. As shown by mass spectrometry, the number of altered
peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For
telmisartan, there were 108 peptide changes in plasma and 363 in the kidney
versus placebo. Linagliptin up-regulated peptides derived from collagen type
I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a
potential downstream target of atrial natriuretic peptide, whereas telmisartan
up-regulated angiotensin II. A second study was conducted to confirm these
findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats
treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was
as effective as DPP-4 genetic deficiency in terms of albuminuria reduction.
Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD
progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying
pathways seem to be different.Dipeptidylpeptidase 4 (DPP4)-Inhibitoren verzögern glukoseunabhängig die
Progression des chronischen Nierenversagens (CNV) in experimentellen Modellen
der diabetischen Nephropathie. In dieser Arbeit wurden renoprotektive Effekte
des DPP4-Inhibitors Linagliptin in einem nicht-diabetischen 5/6-Nephrektomie
Rattenmodell untersucht und mit dem Angiotensin-II-Rezeptorblocker (ARB)
Telmisartan verglichen. Die Tiere wurden in 4 Gruppen aufgeteilt: Sham-
Operation plus Placebo; 5/6-Nephrektomie plus Placebo; 5/6-Nephrektomie plus
Linagliptin; und 5/6-Nephrektomie plus Telmisartan. Die Behandlung mit
Linagliptin führte zu einer signifikanten Reduktion (48%) der interstitiellen
Fibrose in der Niere im Vergleich zu Placebo behandelten Tieren. Telmisartan
bewirkte eine numerische Reduktion (24%) der renalen interstitiellen Fibrose,
die jedoch nicht statistisch signifikant war. Die Albumin-Kreatinin-Ratio im
Urin wurde sowohl durch Linagliptin (66%) als auch durch Telmisartan (92%)
signifikant gesenkt. Die Behandlung mit Telmisartan war mit einer
signifikanten Reduktion des Blutdrucks verbunden, bei mit Linagliptin
behandelten Tieren war diesbezüglich kein Effekt zu beobachten. Eine
massenspektrometrische Analyse von Peptiden zeigte dass Linagliptin im
Vergleich zu Placebo eine unterschiedliche Regulation von 552 plasmatischen
und 320 renalen Peptiden bewirkte. Im Vergleich zu Placebo, fanden sich bei
Telmisartan 108 plasmatische und 363 renale unterschiedlich regulierte
Peptide. Linagliptin führte zu einer Hochregulation von Peptiden des Typ 1
Kollagens, des Apolipoproteins C1 und des Heterogeneous Nuclear
Ribonucleoproteins A2/B1, einem in der Signalkaskade des atrialen
natriuretischen Peptids involviertem Faktor. Telmisartan war mit einer
Hochregulation von Angiotensin-II verbunden. Zur Bestätigung der Ergebnisse
wurde in einer weiteren Studie die Wirkung von Linagliptinin in
5/6-nephrektomierten Wildtyp- und DPP4-defizienten Ratten untersucht.
Linagliptin zeigte sich in Wildtyp-Ratten genauso wirksam wie in den DPP4
defizienten Tieren. Zusammenfassend entfaltete Linagliptin im Vergleich zu
Telmisartan vergleichbare positive Effekte auf die Progression des CNVs in
nicht-diabetischen Ratten mit 5/6-Nephrektomie. Daten dieser Studie deuten
ferner darauf hin, dass die der Renoprotektion zugrunde liegenden Mechanismen
der beiden untersuchten Pharmaka über unterschiedliche Signalwege mediiert
werden
Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice
Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference: -2.57 mmHg, 95% CI: -4.98∼ -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95% CI: -10.76∼ -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure
Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice
Dealing with Large Sample Sizes: Comparison of a New One Spot Dot Blot Method to Western Blot
Background: Western blot is the gold standard method to determine individual protein expression levels.
However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and
labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disad-
vantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein.
Methods: In this study we established a one dot two development signals (ODTDS) dot blot method employing two
different signal development systems. The first signal from the protein of interest was detected by horseradish
peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phos-
phatase (AP).
Results: Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between
both methods were low (1.04 - 5.71%) as assessed by coefficient of variation.
Conclusions: ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes
without a reduction in results accuracy
Paternal eNOS deficiency in mice affects glucose homeostasis and liver glycogen in male offspring without inheritance of eNOS deficiency itself
Aims/hypothesis
It was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring’s phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency.
Methods
Heterozygous (+/−) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents.
Results
Global sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/− eNOS fathers. Wild-type male but not female offspring of +/− eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/− eNOS fathers. The endocrine pancreas in wild-type offspring was not affected.
Conclusions/interpretation
Our study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/− eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes