TY - JOUR A1 - Chaykovska, Lyubov A1 - Heunisch, Fabian A1 - von Einem, Gina A1 - Hocher, Carl-Friedrich A1 - Tsuprykov, Oleg A1 - Pavkovic, Mira A1 - Sandner, Peter A1 - Kretschmer, Axel A1 - Chu, Chang A1 - Elitok, Saban A1 - Stasch, Johannes-Peter A1 - Hocher, Berthold T1 - Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium JF - PLoS one N2 - Background The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography. Methods Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charite Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE. Results In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean +/- SD was predictive for the need of dialysis (no dialysis: 89.77 +/- 92.85 mu M/mM, n = 277; need for dialysis: 140.3 +/- 82.90 mu M/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60 +/- 92.50 mu M/mM, n = 280; death during follow-up: 169.88 +/- 81.52 mu M/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02 +/- 93.17 mu M/mM, n = 271; MARE: 146.64 +/- 74.68 mu M/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 pM/mM in patients who developed MARE, required dialysis or died. Conclusions Urinary cGMP/creatinine ratio >= 120 mu M/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes. Y1 - 2018 U6 - https://doi.org/10.1371/journal.pone.0195828 SN - 1932-6203 VL - 13 IS - 4 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Hocher, Berthold A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Zhang, Xiaoli A1 - Tsuprykov, Oleg A1 - Rahnenführer, Jan A1 - Xie, Li A1 - Li, Jian A1 - Hu, Liang A1 - Krämer, Bernhard K. A1 - Hasan, Ahmed A. T1 - Paternal eNOS deficiency in mice affects glucose homeostasis and liver glycogen in male offspring without inheritance of eNOS deficiency itself JF - Diabetologia N2 - 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. KW - eNOS KW - Glucocorticoid receptor KW - Insulin resistance KW - Paternal programming; KW - PGC1a Y1 - 2022 U6 - https://doi.org/10.1007/s00125-022-05700-x SN - 0012-186X SN - 1432-0428 VL - 65 IS - 7 SP - 1222 EP - 1236 PB - Springer CY - New York ER - TY - JOUR A1 - Li, Jian A1 - Tsuprykov, Oleg A1 - Yang, Xiaoping A1 - Hocher, Berthold T1 - Paternal programming of offspring cardiometabolic diseases in later life JF - Journal of hypertension KW - cardiometabolic diseases KW - epigenetics KW - offspring KW - paternal programming KW - spermatogenesis KW - transgenerational effects Y1 - 2016 U6 - https://doi.org/10.1097/HJH.0000000000001051 SN - 0263-6352 SN - 1473-5598 VL - 34 SP - 2111 EP - 2126 PB - Wiley-Blackwell CY - Philadelphia ER -