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Insulin exits skeletal muscle capillaries by fluid-phase transport.
Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS, Wasserman DH
(2018) J Clin Invest 128: 699-714
MeSH Terms: Animals, Antigens, CD, Biological Transport, Capillaries, Diabetes Mellitus, Glucose, Glucose Clamp Technique, Humans, Hyperinsulinism, Image Processing, Computer-Assisted, Insulin, Intravital Microscopy, Kinetics, Male, Mice, Mice, Inbred C57BL, Models, Theoretical, Muscle, Skeletal, Protein Binding, Receptor, Insulin, Rhodamines
Show Abstract · Added March 14, 2018
Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
1 Communities
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21 MeSH Terms
The Spectrum of Histologic Findings in Hepatic Outflow Obstruction.
Gonzalez RS, Gilger MA, Huh WJ, Washington MK
(2017) Arch Pathol Lab Med 141: 98-103
MeSH Terms: Adolescent, Adult, Aged, Budd-Chiari Syndrome, Capillaries, Child, Child, Preschool, Diagnosis, Differential, Female, Fibrosis, Heart Failure, Hepatic Veno-Occlusive Disease, Humans, Infant, Liver, Liver Diseases, Male, Middle Aged, Young Adult
Show Abstract · Added March 14, 2018
CONTEXT - -Cardiac hepatopathy and Budd-Chiari syndrome are 2 forms of hepatic venous outflow obstruction with different pathophysiology but overlapping histologic findings, including sinusoidal dilation and centrilobular necrosis.
OBJECTIVE - -To determine whether a constellation of morphologic findings could help distinguish between the 2 and could suggest the diagnoses in previously undiagnosed patients.
DESIGN - -We identified 26 specimens with a diagnosis of cardiac hepatopathy and 23 with a diagnosis of Budd-Chiari syndrome. Slides stained with hematoxylin and eosin and with trichrome were evaluated for several distinctive histologic findings.
RESULTS - -Features common to both forms of hepatic outflow obstruction included sinusoidal dilation and portal tract changes of fibrosis, chronic inflammation, and bile ductular reaction. Histologic findings significantly more common in cardiac hepatopathy included pericellular/sinusoidal fibrosis and fibrosis around the central vein. Only centrilobular hepatocyte dropout/necrosis was significantly more common in Budd-Chiari, regardless of duration.
CONCLUSIONS - -The finding of pericellular/sinusoidal fibrosis in cardiac hepatopathy compared with Budd-Chiari is not unexpected, given the chronic nature of most cardiac hepatopathy. Portal tract changes are common in both forms of hepatic outflow obstruction and should not deter one from making the diagnosis of hepatic outflow obstruction. Fibrosis along sinusoids and around the central vein may be suggestive of cardiac hepatopathy in biopsies from patients without a prior diagnosis.
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19 MeSH Terms
Vasodilator-responsive idiopathic pulmonary arterial hypertension: evidence for a new disease?
Brittain EL, Hemnes AR
(2015) Ann Intern Med 162: 148-9
MeSH Terms: Capillaries, Familial Primary Pulmonary Hypertension, Female, Humans, Male, Microcirculation, Vasodilator Agents
Added February 10, 2015
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7 MeSH Terms
Shear stress is normalized in glomerular capillaries following ⅚ nephrectomy.
Ferrell N, Sandoval RM, Bian A, Campos-Bilderback SB, Molitoris BA, Fissell WH
(2015) Am J Physiol Renal Physiol 308: F588-93
MeSH Terms: Animals, Blood Pressure, Capillaries, Hematocrit, Hemorheology, Kidney Glomerulus, Male, Nephrectomy, Rats, Wistar, Renal Circulation, Renal Insufficiency, Stress, Mechanical
Show Abstract · Added February 22, 2016
Loss of significant functional renal mass results in compensatory structural and hemodynamic adaptations in the nephron. While these changes have been characterized in several injury models, how they affect hemodynamic forces at the glomerular capillary wall has not been adequately characterized, despite their potential physiological significance. Therefore, we used intravital multiphoton microscopy to measure the velocity of red blood cells in individual glomerular capillaries of normal rats and rats subjected to ⅚ nephrectomy. Glomerular capillary blood flow rate and wall shear stress were then estimated using previously established experimental and mathematical models to account for changes in hematocrit and blood rheology in small vessels. We found little change in the hemodynamic parameters in glomerular capillaries immediately following injury. At 2 wk postnephrectomy, significant changes in individual capillary blood flow velocity and volume flow rate were present. Despite these changes, estimated capillary wall shear stress was unchanged. This was a result of an increase in capillary diameter and changes in capillary blood rheology in nephrectomized rats.
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12 MeSH Terms
Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL, Zhang W
(2014) FASEB J 28: 3579-88
MeSH Terms: Animals, Animals, Congenic, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Choroid Plexus, Endocytosis, Endothelial Cells, Female, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration, Neurons, Pregnancy, Selenium, Selenoprotein P
Show Abstract · Added September 28, 2015
Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.
© FASEB.
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21 MeSH Terms
EIF2AK4 mutations in pulmonary capillary hemangiomatosis.
Best DH, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, Robbins IM, Elliott CG
(2014) Chest 145: 231-236
MeSH Terms: Adolescent, Adult, Capillaries, Exome, Female, Heterozygote, Humans, Lung Diseases, Lung Transplantation, Male, Mutation, Neovascularization, Pathologic, Parents, Pedigree, Protein-Serine-Threonine Kinases, Siblings, Vascular Diseases
Show Abstract · Added May 29, 2014
BACKGROUND - Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.
METHODS - We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.
RESULTS - Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.
CONCLUSIONS - Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.
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17 MeSH Terms
NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury.
Nlandu Khodo S, Dizin E, Sossauer G, Szanto I, Martin PY, Feraille E, Krause KH, de Seigneux S
(2012) J Am Soc Nephrol 23: 1967-76
MeSH Terms: Animals, Antioxidants, Apoptosis, Atrophy, Capillaries, Fibrosis, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Kidney Diseases, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidase 4, NADPH Oxidases, NF-E2-Related Factor 2, Oxidative Stress, Ureteral Obstruction, Vascular Endothelial Growth Factor A
Show Abstract · Added December 26, 2018
NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-β1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1α and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.
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MeSH Terms
Muscle-specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance.
Bonner JS, Lantier L, Hasenour CM, James FD, Bracy DP, Wasserman DH
(2013) Diabetes 62: 572-80
MeSH Terms: Animals, Blood Glucose, Capillaries, Gene Deletion, Hypoglycemic Agents, Insulin, Insulin Resistance, Mice, Mice, Inbred C57BL, Muscle Cells, Muscle, Skeletal, Myocardium, Signal Transduction, Vascular Endothelial Growth Factor A
Show Abstract · Added March 18, 2013
Muscle insulin resistance is associated with a reduction in vascular endothelial growth factor (VEGF) action and muscle capillary density. We tested the hypothesis that muscle capillary rarefaction critically contributes to the etiology of muscle insulin resistance in chow-fed mice with skeletal and cardiac muscle VEGF deletion (mVEGF(-/-)) and wild-type littermates (mVEGF(+/+)) on a C57BL/6 background. The mVEGF(-/-) mice had an ~60% and ~50% decrease in capillaries in skeletal and cardiac muscle, respectively. The mVEGF(-/-) mice had augmented fasting glucose turnover. Insulin-stimulated whole-body glucose disappearance was blunted in mVEGF(-/-) mice. The reduced peripheral glucose utilization during insulin stimulation was due to diminished in vivo cardiac and skeletal muscle insulin action and signaling. The decreased insulin-stimulated muscle glucose uptake was independent of defects in insulin action at the myocyte, suggesting that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion. The deletion of VEGF in cardiac muscle did not affect cardiac output. These studies emphasize the importance for novel therapeutic approaches that target the vasculature in the treatment of insulin-resistant muscle.
2 Communities
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14 MeSH Terms
eNOS deficiency predisposes podocytes to injury in diabetes.
Yuen DA, Stead BE, Zhang Y, White KE, Kabir MG, Thai K, Advani SL, Connelly KA, Takano T, Zhu L, Cox AJ, Kelly DJ, Gibson IW, Takahashi T, Harris RC, Advani A
(2012) J Am Soc Nephrol 23: 1810-23
MeSH Terms: Albuminuria, Angiotensin-Converting Enzyme Inhibitors, Animals, Capillaries, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Disease Models, Animal, Glucose, Humans, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type III, Podocytes, Renin-Angiotensin System, Vascular Endothelial Growth Factor Receptor-2, rho GTP-Binding Proteins
Show Abstract · Added January 28, 2014
Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS(-/-) mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS(-/-) mice, even though it inhibited glomerular capillary enlargement in both. In eNOS(-/-) mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS(-/-) mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS(-/-) glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.
1 Communities
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19 MeSH Terms
Validation of the Oxford classification of IgA nephropathy.
Herzenberg AM, Fogo AB, Reich HN, Troyanov S, Bavbek N, Massat AE, Hunley TE, Hladunewich MA, Julian BA, Fervenza FC, Cattran DC
(2011) Kidney Int 80: 310-7
MeSH Terms: Adolescent, Adult, Analysis of Variance, Antihypertensive Agents, Atrophy, Biopsy, Canada, Capillaries, Chi-Square Distribution, Female, Fibrosis, Glomerular Filtration Rate, Glomerulonephritis, IGA, Glomerulosclerosis, Focal Segmental, Humans, Immunosuppressive Agents, Kidney, Least-Squares Analysis, Logistic Models, Male, Mesangial Cells, Middle Aged, Odds Ratio, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Reproducibility of Results, Retrospective Studies, Severity of Illness Index, Terminology as Topic, Time Factors, United States, Young Adult
Show Abstract · Added February 25, 2014
The Oxford classification of IgA nephropathy (IgAN) identified four pathological elements that were of prognostic value and additive to known clinical and laboratory variables in predicting patient outcome. These features are segmental glomerulosclerosis/adhesion, mesangial hypercellularity, endocapillary proliferation, and tubular atrophy/interstitial fibrosis. Here, we tested the Oxford results using an independent cohort of 187 adults and children with IgAN from 4 centers in North America by comparing the performance of the logistic regression model and the predictive value of each of the four lesions in both data sets. The cohorts had similar clinical and histological findings, presentations, and clinicopathological correlations. During follow-up, however, the North American cohort received more immunosuppressive and antihypertensive therapies. Identifying patients with a rapid decline in the rate of renal function using the logistic model from the original study in the validation data set was good (c-statistic 0.75), although less precise than in the original study (0.82). Individually, each pathological variable offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor. Thus, this North American cohort validated the Oxford IgAN classification and supports its utilization. Further studies are needed to determine the relationship to the impact of treatment and to define the value of the mesangial hypercellularity score.
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33 MeSH Terms