Dataset Information

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-13C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

ABSTRACT: Metabolic sex differences have recently been shown to be particularly important in tailoring treatment strategies. Sex has a major effect on fat turnover rates and plasma lipid delivery in the body. Differences in kidney structure and transporters between male and female animals have been found. Here we investigated sex-specific renal pyruvate metabolic flux and whole-kidney functional status in age-matched healthy Wistar rats. Blood oxygenation level-dependent and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) were used to assess functional status. Hyperpolarized [1-13C]pyruvate was used to assess the metabolic differences between male and female rats. Female rats had a 41% ± 3% and 41% ± 5% lower absolute body and kidney weight, respectively, than age-matched male rats. No difference was seen between age-matched male and female rats in the kidney-to-body weight ratio. A 56% ± 11% lower lactate production per mL/100?mL/min was found in female rats than in age-matched male rats measured by hyperpolarized magnetic resonance and DCE MRI. Female rats had a 33% ± 11% higher glomerular filtration rate than age-matched male rats measured by DCE MRI. A similar renal oxygen tension (T2*) was found between age-matched male and female rats as shown by blood oxygenation level-dependent MRI. The results were largely independent of the pyruvate volume and the difference in body weight. This study shows an existing metabolic difference between kidneys in age-matched male and female rats, which indicates that sex differences need to be considered when performing animal experiments.

SUBMITTER: Wen Y

PROVIDER: S-EPMC7138520 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-<sup>13</sup>C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

Wen Yibo Y Qi Haiyun H Østergaard Mariager Christian C Mose Nielsen Per P Bonde Bertelsen Lotte L Stødkilde-Jørgensen Hans H Laustsen Christoffer C

Tomography (Ann Arbor, Mich.) 20200301 1

Metabolic sex differences have recently been shown to be particularly important in tailoring treatment strategies. Sex has a major effect on fat turnover rates and plasma lipid delivery in the body. Differences in kidney structure and transporters between male and female animals have been found. Here we investigated sex-specific renal pyruvate metabolic flux and whole-kidney functional status in age-matched healthy Wistar rats. Blood oxygenation level-dependent and dynamic contrast-enhanced (DCE ...[more]

PMID: 32280745

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Project description:Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer's disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6?months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p?<?0.01) and increased conversion from pyruvate to lactate (p?<?0.001) in the brain. The hippocampus and striatum showed the highest conversion ratio. The functional integrity of the blood-brain barrier tested by dynamic contrast-enhanced MR imaging showed no difference to the control. Lactate was increased in the cortex (p?<?0.01) and striatum (p?<?0.05), while PDH activity was decreased in the cortex (p?<?0.01) and striatum (p?<?0.001) and the phosphorylated PDH was increased in the striatum (p?<?0.05). Mice fed HFD showed less efficiency in learning memory compared with control (p?<?0.05). To determine whether hyperpolarized 13C-pyruvate magnetic resonance (MR) spectroscopy could detect a much earier event in the brain. Mice fed HFD for 3?months did not show a detectable cognitive decline in water maze based learning memory. Hyperpolarized [1-13C] pyruvate MR spectroscopy showed increased lactate conversion (P?<?.001), but no difference in cerebral perfusion. These results suggest that the increased hyperpolarized [1-13C] lactate signal in the brain of HFD-fed mice represent that altered metabolic alteration toward to glycolysis and hypoperfusion by the long-term metabolic stress by HFD further promote to glycolysis. The hyperpolarized [1-13C] pyruvate MR spectroscopy can be used to monitor the brain metabolism and will provide information helpful to understand the disease process.

Project description:MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, kPL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-13 C]pyruvate parameters (SNR, kPL , bolus characteristics) in the human prostate.

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Project description:This study was designed to determine the effects of deuteration in pyruvate on exchange reactions in alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and flux through pyruvate dehydrogenase (PDH). Although deuteration of a 13C enriched substrate is commonly used to increase the lifetime of a probe for hyperpolarization experiments, the potential impact of kinetic isotope effects on such substitutions has not been studied in detail. Metabolism of deuterated pyruvate was investigated in isolated rat hearts. Hearts were perfused with a 1:1 mixture of [U-13C3]pyruvate and [2-13C1]pyruvate or a 1:1 mixture of [U-13C3]pyruvate plus [2-13C1, U-2H3]pyruvate for 30?min before being freeze clamped. Another set of hearts received [2-13C1, U-2H3]pyruvate and was freeze-clamped at 3?min or 6?min. Tissue extracts were analyzed by 1H and 13C{1H} NMR spectroscopy. The chemical shift isotope effect of 2H was monitored in the 13C NMR spectra of the C2 resonance of lactate and alanine plus the C5 of glutamate. There was little kinetic isotope effect of 2H in pyruvate on flux through PDH, LDH or ALT as detected by the distribution of 13C, but the distribution of 2H differed markedly between alanine and lactate. At steady-state, alanine was a mixture of deuterated species, while lactate was largely perdeuterated. Consistent with results at steady-state, hearts freeze-clamped at 3?min or 6?min showed rapid removal of deuterium in alanine but not in lactate. Metabolism of hyperpolarized [1-13C1]pyruvate was compared to [1-13C1,U-2H3]pyruvate in isolated hearts. Consistent with the results from tissue extracts, there was little effect of deuteration on the kinetics of appearance of lactate, alanine or bicarbonate, but there was a small, time-dependent upfield chemical shift in the HP[1-13C1]alanine signal reflecting exchange of methyl deuterons with water protons. Together, these results demonstrate that (1) the kinetics of pyruvate metabolism in hearts detected by 13C NMR are not affected by replacement of the pyruvate methyl protons with deuterons and (2) that the loss of deuterium from the methyl position occurs rapidly during the conversion of pyruvate to alanine. The majority of the deuterium atoms are lost on the time-scale of a hyperpolarization experiment.

Dataset Information

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-13C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

Publications

Sex Differences in Kidney Function and Metabolism Assessed Using Hyperpolarized [1-<sup>13</sup>C]Pyruvate Interleaved Spectroscopy and Nonspecific Imaging.

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