Cortical Content Research Articles

Renal ischemia‐reperfusion (I/R) injury induces a rapid activation of local inflammatory markers and causes increased peritubular permeability.

Local cytokines were measured in renal hilar lymph and in cortex after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion. The effect of I/R on size selectivity for proteins in glomerular and peritubular capillaries were estimated using HPLC and mass spectrometry. Whereas all measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and approached control levels after 120 min reperfusion, the responses were differentiated. IL‐1beta, MCP‐1 and leptin were markedly increased in plasma before reperfusion, reflecting an extra renal response possibly induced by afferent renal nerve activity from the ischemic kidney. The cortical cytokine content also reached high levels before reperfusion suggesting proteolytic release of local stores. However, only TNF‐alpha showed increased lymph to plasma ratio (L/P>;1) following 30 min reperfusion indicating release of mediators directly into the bloodstream in agreement with abundant cytokine staining of glomerular and peritubular capillaries. The cytokine levels were paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine indicating temporarily reduced size selectivity of both glomerular and peritubular capillaries. In conclusion, short time renal ischemia is a strong trigger for a local as well as systemic inflammatory reaction.

An integrated map of corticotropin‐releasing hormone signaling pathway

An integrated map of corticotropin‐releasing hormone signaling pathway

Physiological skeletal gains and losses in rat mothers during pregnancy and lactation are not observed following uteroplacental insufficiency

Fluctuations in maternal bone mass during pregnancy and lactation facilitate calcium transfer to offspring. Uteroplacental insufficiency causes fetal growth restriction and programs poor adult bone health. We aimed to characterise maternal skeletal phenotype during normal pregnancy and pregnancy complicated by uteroplacental insufficiency. Uteroplacental restriction (Restricted) or sham surgery (Control) was performed on gestational Day 18 (term=22 days) in pregnant Wistar-Kyoto rats. Maternal right femurs were collected on embryonic Day 20, postnatal Day 1 and Weeks 5, 7 and 9 postnatal. Dual-energy X-ray absorptiometry was used to quantify global bone mineral content, density and body composition. Peripheral quantitative computed tomography was utilised to determine trabecular and cortical content, density, circumferences and strength. Control rats exhibited expected reductions in trabecular and cortical content, density and bone strength from embryonic Day 20 to postnatal Day 1 (P<0.05). These skeletal alterations were absent in Restricted rats. By postnatal Day 7, bone parameters in Control and Restricted rats were not different from non-pregnant rats, indicating restoration of maternal bone. The lack of bone loss in mothers suffering uteroplacental insufficiency suggests that calcium transfer to pups would be impaired. This reduction in calcium availability is a likely contributor to the programming of poor adult bone health in growth-restricted offspring.

A reference-channel based methodology to improve estimation of event-related hemodynamic response from fNIRS measurements

Functional near-infrared spectroscopy (fNIRS) uses near-infrared light to measure cortical concentration changes in oxygenated (HbO) and deoxygenated hemoglobin (HbR) held to be correlated with cognitive activity. Providing a parametric depiction of such changes in the classic form of stimulus-evoked hemodynamic responses (HRs) can be attained with this technique only by solving two problems. One problem concerns the separation of informative optical signal from structurally analogous noise generated by a variety of spurious sources, such as heart beat, respiration, and vasomotor waves. Another problem pertains to the inherent variability of HRs, which is notoriously contingent on the type of experiment, brain region monitored, and human phenotype. A novel method was devised in the present context to solve both problems based on a two-step algorithm combining the treatment of noise-only data extrapolated from a reference-channel and a Bayesian filter applied on a per-trial basis. The present method was compared to two current methods based on conventional averaging, namely, a typical averaging method and an averaging method implementing the use of a reference-channel. The result of the comparison, carried out both on artificial and real data, revealed a sensitive accuracy improvement in HR estimation using the present method relative to each of the other methods.

Diversity in the fertilization envelopes of echinoderms.

Cell surface changes in an egg at fertilization are essential to begin development and for protecting the zygote. Most fertilized eggs construct a barrier around themselves by modifying their original extracellular matrix. This construction usually results from calcium-induced exocytosis of cortical granules, the contents of which in sea urchins function to form the fertilization envelope (FE), an extracellular matrix of cortical granule contents built upon a vitelline layer scaffold. Here, we examined the molecular mechanism of this process in sea stars, a close relative of the sea urchins, and analyze the evolutionary changes that likely occurred in the functionality of this structure between these two organisms. We find that the FE of sea stars is more permeable than in sea urchins, allowing diffusion of molecules in excess of 2 megadaltons. Through a proteomic and transcriptomic approach, we find that most, but not all, of the proteins present in the sea urchin envelope are present in sea stars, including SFE9, proteoliaisin, and rendezvin. The mRNAs encoding these FE proteins accumulated most densely in early oocytes, and then beginning with vitellogenesis, these mRNAs decreased in abundance to levels nearly undetectable in eggs. Antibodies to the SFE9 protein of sea stars showed that the cortical granules in sea star also accumulated most significantly in early oocytes, but different from sea urchins, they translocated to the cortex of the oocytes well before meiotic initiation. These results suggest that the preparation for cell surface changes in sea urchins has been shifted to later in oogenesis, and perhaps reflects the meiotic differences among the species-sea star oocytes are stored in prophase of meiosis and fertilized during the meiotic divisions, as in most animals, whereas sea urchins are one of the few taxons in which eggs have completed meiosis prior to fertilization.

A Possible Potentiating Antidepressant Effect of Venlafaxine by Recombinant Rat Leptin in a Rat Model of Chronic Mild Stress

Abstract: The present study was designed to investigate the possible changes in forced swimming test (FST), prefrontal cortical glutamate and gamma amino-butyric acid (GABA) contents by leptin and/or venlafaxine in chronic mild stress (CMS)-induced anhedonia in male albino rats. They were divided into 5 groups: the first group was not exposed to CMS, the second group received normal saline with exposure to CMS, the third group received leptin 1 mg/kg/day intraperitoneally (ip) for 3 weeks after CMS induced anhedonia was assesed by sucrose consumption test, the fourth group received venlafaxine 8 mg/kg/day ip for 3 weeks after CMS protocol, and the fifth group was received both medications for 3 weeks. Leptin and/or venlafaxine restored the changes in sucrose consumption test, behavioural assessment by forced swimming test (FST) as well as prefrontal cortical GABA and glutamate contents in the control stressed group. Furthermore, combination of both treatments seems to be more efficacious than venlafaxine alone in these parameters. In conclusion,these results showed a potential antidepressant role of leptin and beneficial therapeutic interaction with venlafaxine by affecting the GABA and glutamate level in prefrontal cortex. These actions could make leptin a potentially valuable drug for the treatment of depression.

The efference cascade, consciousness, and its self: naturalizing the first person pivot of action control.

The 20 billion neurons of the neocortex have a mere hundred thousand motor neurons by which to express cortical contents in overt behavior. Implemented through a staggered cortical “efference cascade” originating in the descending axons of layer five pyramidal cells throughout the neocortical expanse, this steep convergence accomplishes final integration for action of cortical information through a system of interconnected subcortical way stations. Coherent and effective action control requires the inclusion of a continually updated joint “global best estimate” of current sensory, motivational, and motor circumstances in this process. I have previously proposed that this running best estimate is extracted from cortical probabilistic preliminaries by a subcortical neural “reality model” implementing our conscious sensory phenomenology. As such it must exhibit first person perspectival organization, suggested to derive from formating requirements of the brain's subsystem for gaze control, with the superior colliculus at its base. Gaze movements provide the leading edge of behavior by capturing targets of engagement prior to contact. The rotation-based geometry of directional gaze movements places their implicit origin inside the head, a location recoverable by cortical probabilistic source reconstruction from the rampant primary sensory variance generated by the incessant play of collicularly triggered gaze movements. At the interface between cortex and colliculus lies the dorsal pulvinar. Its unique long-range inhibitory circuitry may precipitate the brain's global best estimate of its momentary circumstances through multiple constraint satisfaction across its afferents from numerous cortical areas and colliculus. As phenomenal content of our sensory awareness, such a global best estimate would exhibit perspectival organization centered on a purely implicit first person origin, inherently incapable of appearing as a phenomenal content of the sensory space it serves.

Adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity.

Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.

Molecular events in matrix protein metabolism in the aging kidney

We explored molecular events associated with aging-induced matrix changes in the kidney. C57BL6 mice were studied in youth, middle age, and old age. Albuminuria and serum cystatin C level (an index of glomerular filtration) increased with aging. Renal hypertrophy was evident in middle-aged and old mice and was associated with glomerulomegaly and increase in mesangial fraction occupied by extracellular matrix. Content of collagen types I and III and fibronectin was increased with aging; increment in their mRNA varied with the phase of aging. The content of ZEB1 and ZEB2, collagen type I transcription inhibitors, and their binding to the collagen type Iα2 promoter by ChIP assay also showed age-phase-specific changes. Lack of increase in mRNA and data from polysome assay suggested decreased degradation as a potential mechanism for kidney collagen type I accumulation in the middle-aged mice. These changes occurred with increment in TGFβ mRNA and protein and activation of its SMAD3 pathway; SMAD3 binding to the collagen type Iα2 promoter was also increased. TGFβ-regulated microRNAs (miRs) exhibited selective regulation. The renal cortical content of miR-21 and miR-200c, but not miR-192, miR-200a, or miR-200b, was increased with aging. Increased miR-21 and miR-200c contents were associated with reduced expression of their targets, Sprouty-1 and ZEB2, respectively. These data show that aging is associated with complex molecular events in the kidney that are already evident in the middle age and progress to old age. Age-phase-specific regulation of matrix protein synthesis occurs and involves matrix protein-specific transcriptional and post-transcriptional mechanisms.

Optimizing T1-weighted imaging of cortical myelin content at 3.0T

With increases in the sensitivity and resolution of anatomical MRI for the brain, methods for mapping the organization of the cerebral cortex by imaging its myelin content have emerged. This identifies major sensory and motor regions and could be used in studies of cortical organization, particularly if patterns of myelination can be visualized over the cortical surface robustly in individual subjects. The imaging problem is difficult, however, because of the relative thinness of the cerebral cortex and the low intracortical tissue contrast. In this paper, we optimize the contrast of T(1)-weighted MRI to help better visualize patterns of myelination. We measure a small but statistically significant difference in T(1) of 171 ± 40 ms between cortical regions with low and high myelin contents in the human cortex at 3T, and then perform simulations to choose parameters for an inversion-recovery pulse sequence that utilizes this T(1) difference to increase contrast within the cortex. We show that lengthening the delay between signal acquisition and the next inversion pulse in the sequence increases intracortical contrast more effectively than does image averaging. Using the optimized sequence, we show that major myelinated regions that are relatively thick, such as the primary motor and auditory regions, can be visualized well in individuals at 3T using whole-cortex 3D images made at 1mm isotropic resolution, while thinner regions, such as the primary visual cortex, can be visualized using targeted 3D images made at 0.5mm isotropic resolution. Our findings demonstrate that patterns of myelination can be better visualized in individual subjects when the imaging is optimized to highlight intracortical contrast and can help to pave the way for the creation of matched maps of microanatomy and function in the cortex of living individual humans.

P16 Tadalafil stimulates hydrogen sulfide-AMPK pathway to inhibit high glucose stimulation of protein synthesis in mouse podocytes

Kidney injury is one of the most serious complications of diabetes. Current therapies only slow down but do not stop its progression to end stage kidney failure; thus, there is a need for novel approaches. Accumulation of extracellular matrix proteins, e.g., laminin, fibronectin, contributes to the loss of functioning parenchyma and progressive loss of kidney function in diabetes. We have recently reported that H2S inhibits high glucose-induced increase in synthesis of proteins including matrix proteins (H.J. Lee et al., J. Biol. Chem. 287 (2012) 4451). We wish to identify H2S generating agents that can be used in humans to treat diabetic kidney disease. We hypothesized that tadalafil, a H2S donor and phosphodiesterase 5 (PDE5) inhibitor, inhibits high glucose stimulation of synthesis of proteins including ECM proteins by generating H2S in mouse kidney podocytes. High glucose (30 mM), but not equimolar mannitol, significantly promoted global protein synthesis, cellular hypertrophy and expression of laminin-γ1 and fibronectin. These events were inhibited by 10 μM tadalafil. Because mRNA translation is rate-limiting for protein synthesis, we examined tadalafil effect on events in translation. Tadalafil abrogated high glucose-induced mTORC1 activation as indicated by phosphorylation of p70S6 kinase and 4E-BP1; both these events are important for the initiation phase of translation. Tadalafil reversed high glucose-induced changes in the phosphorylation of eEF2 and eEF2 kinase, which regulate the elongation phase of translation. Upstream regulators of mTORC1 were investigated. Tadalafil stimulated activating phosphorylation of AMPK in a dose dependent manner, peaking at 10 μM. Pre-incubation with Compound C, an AMPK inhibitor, completely abolished tadalafil effect on high glucose stimulation of events in mRNA translation as well as global protein and laminin synthesis. Tadalafil-induced AMPK phosphorylation was abolished by dl -propargylglycine (PAG), an inhibitor of cystathionine γ lyase (CSE), a H2S generating enzyme. Tadalafil rapidly increased CSE protein expression in 1 h which was inhibited by cycloheximide but not actinomycin-D, suggesting regulation at the level of mRNA translation. In an enzymatic assay, PAG abrogated tadalafil stimulation of generation of H2S. PAG completely abolished tadalafil effect on high glucose stimulation of events in mRNA translation as well as global protein and laminin synthesis. Tadalafil is a PDE5 inhibitor that increases cGMP content. ODQ, an inhibitor of guanylyl cyclase that generates cGMP, abolished tadalafil induction of AMPK phosphorylation. ODQ abrogated tadalafil inhibition of high glucose-induced increase in laminin expression. Renal cortical content of cystathionine β synthase (CBS) and CSE, H2S generating enzymes, was significantly reduced in the kidney in mice with type 1 or type 2 diabetes. Our data show that tadalafil stimulates H2S-AMPK axis to inhibit mTORC1 and mRNA translation leading to amelioration of high glucose-induced global and matrix protein increment in renal podocytes. It is likely that tadalafil stimulation of H2S is cGMP-dependent in the podocyte. Future work is needed to define whether tadalafil can ameliorate kidney injury in animal models of diabetes.

Functional near-infrared spectroscopy reveals heterogeneous patterns of language lateralization over frontopolar cortex

Functional near-infrared spectroscopy (fNIRS), a non-invasive neuroimaging optical technique which measures the cortical concentration changes in oxygenated and deoxygenated hemoglobin (O2Hb and HHb, respectively), has been extensively utilized in language studies. Most of these studies investigated the ventrolateral/dorsolateral cortex responses, while few language studies on the frontopolar cortex are reported. The aim of this study was to investigate by fNIRS the frontopolar cortex response to a letter verbal fluency task (VFT) in single healthy subjects to better understand the symmetry/asymmetry of language processing. The O2Hb and HHb changes were measured on 33 University students by a 8-channel fNIRS system. A significant increase in O2Hb (p<0.001), accompanied by a smaller significant decrease in HHb (p<0.001), was observed in each measurement point. However, the laterality index of 21 out of the 33 subjects evidenced a hemispheric dominance (right 9, left 12). Although these results have confirmed a bilateral activation over the frontopolar cortex upon VFT, no clear pattern of lateralization was found. Considering the importance of establishing a response pattern related to cognitive functions in clinical populations, the fNIRS investigation of the frontopolar cortex (and other areas involved in language) in single subject and the use of the laterality index are recommended.

Cortical GABA levels in primary insomnia.

GABA is increasingly recognized as an important neurotransmitter for the initiation and maintenance of sleep. We sought to measure cortical GABA content through proton magnetic resonance spectroscopy (MRS) in persons with and without primary insomnia, and relate brain GABA levels to polysomnographic sleep measures. Two-group comparison study. Outpatient study at a university research clinic. Non-medicated persons with primary insomnia (N = 16) and no sleep complaints (N = 17). Participants kept sleep diaries and a regular time-in-bed schedule for 9 days, culminating in 2 consecutive nights of ambulatory polysomnography and a single proton MRS session. The main outcome measure was occipital GABA/creatine ratios; secondary measures included sleep measurements and relationship between polysomnographically measured time awake after sleep onset and occipital GABA content. The primary insomnia group was distinguished from persons with no sleep complaints on self-reported and polysomnographically measured sleep. The two groups did not differ in age, sex, body mass index, habitual bed- and wake-times, napping, use of caffeine, or use of cigarettes. Mean occipital GABA level was 12% higher in persons with insomnia than in persons without sleep complaints (P < 0.05). In both groups, GABA levels correlated negatively with polysomnographically measured time awake after sleep onset (P < 0.05). Increased GABA levels in persons with insomnia may reflect an allostatic response to chronic hyperarousal. The preserved, negative relationship between GABA and time awake after sleep onset supports this notion, indicating that the possible allostatic response is adaptive.

Effect of systemic kynurenine on cortical spreading depression and its modulation by sex hormones in rat

BackgroundThe aura symptoms in migraine are most likely due to cortical spreading depression (CSD). CSD is favored by NMDA receptor activation and increased cortical excitability. The latter probably explains why migraine with aura may appear when estrogen levels are high, like during pregnancy. Kynurenic acid, a derivative of tryptophan metabolism, is an endogenous NMDA receptor antagonist whose cerebral concentrations can be augmented by systemic administration of its precursor l-kynurenine. ObjectiveTo determine if exogenous administration of l-kynurenine is able to influence KCl-induced CSD in rat, if the effect is sex-dependent and if it differs in females between the phases of the estrous cycle. MethodsAdult Sprague–Dawley rats (n=8/group) received intraperitoneal (i.p.) injections of l-kynurenine (L-KYN, 300mg/kg), L-KYN combined with probenecid (L-KYN+PROB) that increases cortical concentration of KYNA by blocking its excretion from the central nervous system, probenecid alone (PROB, 200mg/kg) or NaCl. Cortical kynurenic acid concentrations were determined by HPLC (n=7). Thirty minutes after the injections, CSDs were elicited by application of 1M KCl over the occipital cortex and recorded by DC electrocorticogram. In NaCl and L-KYN groups, supplementary females were added and CSD frequency was analyzed respective to the phases of the estrous cycle determined by vaginal smears. ResultsIn both sexes, PROB, L-KYN and L-KYN+PROB increased cortical kynurenic acid level. PROB, L-KYN and L-KYN+PROB with increasing potency decreased CSD frequency in female rats, while in males such an effect was significant only for L-KYN+PROB. The inhibitory effect of L-KYN on CSD frequency in females was most potent in diestrus. Conclusionl-Kynurenine administration suppresses CSD, most likely by increasing kynurenic acid levels in the cortex. Females are more sensitive to this suppressive effect of l-kynurenine than males. These results emphasize the role of sex hormones in migraine and open interesting novel perspectives for its preventive treatment.

Glutamate, GABA, and other cortical metabolite concentrations during early abstinence from alcohol and their associations with neurocognitive changes

BackgroundLittle is known about the effects of alcohol dependence on cortical concentrations of glutamate (Glu) or gamma aminobutyric acid (GABA). We used proton magnetic resonance spectroscopy (MRS) to study cross-sectionally and longitudinally the concentrations of these in alcohol dependent individuals (ALC) during early abstinence from alcohol. MethodsTwenty ALC were studied at about one week of abstinence from alcohol (baseline) and 36 ALC at five weeks of abstinence and compared to 16 light/non-drinking controls (LD). Eleven ALC were studied twice during abstinence. Participants underwent clinical interviewing, blood work, neuropsychological testing, structural imaging and single-volume proton MRS at 4Tesla. Absolute concentrations of Glu, GABA and those of other 1H MRS-detectable metabolites were measured in the anterior cingulate (ACC), parieto-occipital cortex (POC) and dorso-lateral prefrontal cortex (DLPFC). Relationships of metabolite levels to drinking severity and neurocognition were also assessed. ResultsALC at baseline had lower concentrations of Glu, N-acetylaspartate (NAA), choline- (Cho) and creatine-containing metabolites (Cr) than LD in the ACC, but had normal GABA and myo-inositol (mI) levels. At five weeks of abstinence, metabolite concentrations were not significantly different between groups. Between one and five weeks of abstinence, Glu, NAA and Cho levels in the ACC increased significantly. Higher cortical mI concentrations in ALC related to worse neurocognitive outcome. ConclusionThese MRS data suggest compromised and regionally specific bioenergetics/metabolism in one-week-abstinent ALC that largely normalizes over four weeks of sustained abstinence. The correlation between mI levels and neurocognition affirms the functional relevance of this putative astrocyte marker.

The role of GPR91 in the Akita model of diabetic nephropathy (DN)

The importance of local tissue metabolism, succinate accumulation and signaling via its receptor GPR91 in the activation of the intra‐renal renin‐angiotensin system (RAS) in DN has been established by our laboratory using the streptozotocin (STZ) model. However, the genetic Akita (A) mouse model of type I diabetes is an excellent alternative to study DN due to lack of the toxic side effects of STZ. In this study we used wild type A (n=6) and GPR91−/− A (A−/−, n=5) mice at 18‐wks of age. Although both groups develop robust hyperglycemia, we observed noticeable decreases in water intake, food intake and urine volume in A−/− mice. Urinary albumin excretion showed 1.69±0.7 fold increase in A group compared to WT and only 1.04±0.2 increase in in A−/− mice. Immunohistochemical analyses of TGFβ found strong glomerular labeling in A but not A−/− kidneys. Whole kidney Western blots demonstrated higher TGFβ content in A mice (1.27±0.3) than A−/− (0.68±0.1). A mice revealed higher cortical renin content (1.37±0.2) than A−/− (1.0±0.1). A significant difference in medullary renin was observed between A (1.34±0.2) and A−/− mice (0.8±0.1). We concluded that GPR91 plays an important role in the pathogenesis of DN.

Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells

Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (30 mm) stimulation of matrix protein synthesis in glomerular epithelial cells. High glucose stimulation of global protein synthesis, cellular hypertrophy, and matrix laminin and type IV collagen content was inhibited by sodium hydrosulfide (NaHS), an H(2)S donor. High glucose activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was inhibited by NaHS. High glucose stimulated mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduction in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation, and dephosphorylation of eEF2; these events were inhibited by NaHS. The role of AMP-activated protein kinase (AMPK), an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phosphorylation reduced by high glucose. Compound C, an AMPK inhibitor, abolished NaHS modulation of high glucose effect on events in mRNA translation as well as global and matrix protein synthesis. NaHS induction of AMPK phosphorylation was inhibited by siRNA for calmodulin kinase kinase β, but not LKB1, upstream kinases for AMPK; STO-609, a calmodulin kinase kinase β inhibitor, had the same effect. Renal cortical content of cystathionine β-synthase and cystathionine γ-lyase, hydrogen sulfide-generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hypertrophy and matrix accumulation. Hydrogen sulfide is a newly identified modulator of protein synthesis in the kidney, and reduction in its generation may contribute to kidney injury in diabetes.

Évaluation du contenu tissulaire rénal en oxygène par la technique IRM BOLD

Blood Oxygen Level-Dependent (BOLD) MRI signal is a new method of renal functional imaging which allows renal cortical and medullary oxygen contents measurement in a noninvasive way and without injection of potentially nephrotoxic contrast product. Several clinical and experimental studies showed its potential interest in measuring renal oxygen content and its variation during different renal injuries, allowing new progress in the comprehension of the pathophysiology of several nephropathies.

Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats

Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones. Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs). Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II. The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity.

Characterization of Mid1 domains for targeting and scaffolding in fission yeast cytokinesis

Division-site selection and contractile-ring assembly are two crucial steps in cytokinesis. In fission yeast, the anillin-like Mid1 protein specifies the division site at the cell equator by assembling cortical nodes, the precursors of the contractile ring. Thus, Mid1 is essential for linking the positional cues for the cleavage site to contractile-ring formation. However, how Mid1 domains cooperate to regulate cytokinesis is poorly understood. Here we unravel the functions of different Mid1 domains (motifs) by a series of truncations. We report that the conserved PH domain stabilizes Mid1 in nodes by binding to lipids and is required for Mid1 cortical localization during interphase in the absence of Cdr2 kinase. Mid1 lacking an internal region that is approximately one third of the full-length protein has higher nuclear and cortical concentration and suppresses the division-site positioning defects in cells with a deletion of the dual-specificity tyrosine-regulated kinase Pom1. The N-terminus of Mid1 physically interacts with cytokinesis node proteins. When fused to cortical node protein Cdr2, Mid1(1-100) is sufficient to assemble cytokinesis nodes and the contractile ring. Collectively, our study recognizes domains regulating Mid1 cortical localization and reveals domains sufficient for contractile-ring assembly.