scholarly journals DHHC21 Deficiency Attenuates Renal Dysfunction During Septic Injury

2021 ◽  
Author(s):  
Xiaoyuan Yang ◽  
Ethan Zheng ◽  
Yonggang Ma ◽  
Victor Chatterjee ◽  
Nuria Villalba ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Vascular Function ◽  
Structural Damage ◽  
Vascular Dysfunction ◽  
Cecal Ligation ◽  
Renal Perfusion ◽  
Loss Of Function ◽  
Optoacoustic Imaging ◽  
Downstream Effector ◽  
And Function

Abstract Renal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21dep/dep) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.

scholarly journals DHHC21 deficiency attenuates renal dysfunction during septic injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaoyuan Yang ◽  
Ethan Zheng ◽  
Yonggang Ma ◽  
Victor Chatterjee ◽  
Nuria Villalba ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Vascular Function ◽  
Structural Damage ◽  
Vascular Dysfunction ◽  
Cecal Ligation ◽  
Renal Perfusion ◽  
Loss Of Function ◽  
Optoacoustic Imaging ◽  
Downstream Effector ◽  
And Function

AbstractRenal dysfunction is one of the most common complications of septic injury. One critical contributor to septic injury-induced renal dysfunction is renal vascular dysfunction. Protein palmitoylation serves as a novel regulator of vascular function. Here, we examined whether palmitoyl acyltransferase (PAT)-DHHC21 contributes to septic injury-induced renal dysfunction through regulating renal hemodynamics. Multispectral optoacoustic imaging showed that cecal ligation and puncture (CLP)-induced septic injury caused impaired renal excretion, which was improved in DHHC21 functional deficient (Zdhhc21dep/dep) mice. DHHC21 deficiency attenuated CLP-induced renal pathology, characterized by tissue structural damage and circulating injury markers. Importantly, DHHC21 loss-of-function led to better-preserved renal perfusion and oxygen saturation after CLP. The CLP-caused reduction in renal blood flow was also ameliorated in Zdhhc21dep/dep mice. Next, CLP promoted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and the activation of its downstream effector ERK, which were blunted in Zdhhc21dep/dep mice. Vasoreactivity analysis revealed that renal arteries from Zdhhc21dep/dep mice displayed reduced constriction response to α1AR agonist phenylephrine compared to those from wild-type mice. Consistently, inhibiting PATs with 2-bromopalmitate caused a blunted vasoconstriction response to phenylephrine in small arteries isolated from human kidneys. Therefore, DHHC21 contributes to impaired renal perfusion and function during septic injury via promoting α1AR palmitoylation-associated vasoconstriction.

scholarly journals Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing

Biomedicines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 4 ◽  
Author(s):  
Ginevra Nannelli ◽  
Marina Ziche ◽  
Sandra Donnini ◽  
Lucia Morbidelli
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Low Grade ◽  
Loss Of Function ◽  
Aldehyde Dehydrogenase 2 ◽  
Main Determinants ◽  
And Function ◽  
Low Grade Inflammation

Endothelial cells are the main determinants of vascular function, since their dysfunction in response to a series of cardiovascular risk factors is responsible for disease progression and further consequences. Endothelial dysfunction, if not resolved, further aggravates the oxidative status and vessel wall inflammation, thus igniting a vicious cycle. We have furthermore to consider the physiological manifestation of vascular dysfunction and chronic low-grade inflammation during ageing, also known as inflammageing. Based on these considerations, knowledge of the molecular mechanism(s) responsible for endothelial loss-of-function can be pivotal to identify novel targets of intervention with the aim of maintaining endothelial wellness and vessel trophism and function. In this review we have examined the role of the detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) in the maintenance of endothelial function. Its impairment indeed is associated with oxidative stress and ageing, and in the development of atherosclerosis and neurodegenerative diseases. Strategies to improve its expression and activity may be beneficial in these largely diffused disorders.

Abstract 099: Functional Remodeling of the Renal Vasculature Precedes the Establishment of Salt-sensitive Hypertension in Eln-deficient Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Elizabeth A Owens ◽  
Li Jie ◽  
Beverly Reyes ◽  
Elisabeth J Van Bockstaele ◽  
Patrick Osei-Owusu
Keyword(s):  
Blood Pressure ◽  
Structural Damage ◽  
Vascular Dysfunction ◽  
Renal Perfusion ◽  
Dietary Sodium ◽  
Intraluminal Pressure ◽  
Renal Vasculature ◽  
Salt Loading ◽  
Vascular Stiffening ◽  
Renal Vascular

Vascular stiffening due to elastin deficiency is a leading risk for hypertension and chronic kidney disease (CKD). However, the mechanisms by which elastin deficiency is involved in the pathogenesis of hypertension and/or CKD are poorly understood. Here, we used elastin heterozygous mice ( Eln+/- ), an animal model of elastin insufficiency, to test the hypothesis that renal dysfunction due to elastin deficiency occurs independently of and precedes the development of hypertension in this mouse model. We assessed blood pressure (BP) and renal hemodynamics in 30-day (P30) and 12-week old anesthetized male and female mice. At P30, mean blood pressure of Eln+/- was similar to wild type (WT) controls ( Eln+/- , 79 ± 5 vs. WT, 69±3 mmHg, P = 0.06); however, renal blood flow was lower ( Eln+/- 2.9 ± 0.2 vs. WT 4.0 ± 0.5 mL/min/g KW, P = 0.03) whereas renal vascular resistance (RVR; Eln+/- 29 ± 3 vs. WT 18 ± 3 mmHg/mL/min/g KW, P = 0.03) was augmented at baseline in Eln+/- mice. At 12 wks old, RVR remained elevated while filtration fraction was higher in male Eln+/- relative to WT mice ( Eln+/- 44 ± 3 vs. WT 38±5 % P = 0.07). Eln+/- mice showed isolated systolic hypertension that was evident only at nighttime ( Eln+/- 136 ± 2 vs. WT 112 ± 6 mmHg, P <0.01). Acute salt loading with 6% dietary sodium increased daytime systolic blood pressure only in male Eln+/- mice ( Eln+/- 118 ± 5 vs. WT 102 ± 6 mmHg, P = 0.03), causing a rightward shift and blunted slope of the pressure-natriuresis curve. Renal interlobar artery basal tone and myogenic response to increasing intraluminal pressure at P10 were similar ( Eln+/- 78 ± 3 vs. WT 67 ± 6 % P = 0.06) whereas they were augmented at P30 ( Eln+/- 63 ± 4 vs. WT 49 ± 6 % P = 0.05) and at 12 wks old in Eln+/- mice ( Eln+/- 50 ± 2 vs. WT 33 ± 3 % P < 0.01), and normalized by the AT1R blocker, candesartan ( Eln+/- 22 ± 9 vs. WT 8 ± 5 % P = 0.10). We conclude that AT1R mediates augmented mechanotransduction and renal vascular dysfunction due to Eln insufficiency that in turn contribute to altered renal sodium handling and increased BP. Such prolonged systemic BP elevation leads to glomerular structural damage due to high renal perfusion pressure. Therefore, therapies that target the AT1R to control BP in patients with elastin deficiency may be beneficial in preventing hypertension-evoked kidney damage.

Vascular dysfunction in S1P2 sphingosine 1-phosphate receptor knockout mice

2007 ◽  
Vol 292 (1) ◽  
pp. R440-R446 ◽  
Author(s):  
John N. Lorenz ◽  
Lois J. Arend ◽  
Rachel Robitz ◽  
Richard J. Paul ◽  
A. John MacLennan
Keyword(s):  
Knockout Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Morphology ◽  
Relative Contribution ◽  
Sphingosine 1 Phosphate ◽  
In Vivo Analysis ◽  
And Function ◽  
Isometric Forces

There is growing evidence that sphingosine 1-phosphate (S1P) plays an important role in regulating the development, morphology, and function of the cardiovascular system. There is little data, however, regarding the relative contribution of endogenous S1P and its cognate receptors (referred to as S1P1–5) to cardiovascular homeostasis. We used S1P2 receptor knockout mice (S1P2−/−) to evaluate the role of S1P2 in heart and vascular function. There were no significant differences in blood pressure between wild-type and S1P2−/− mice, measured in awake mice. Cardiac function, evaluated in situ by using a Millar catheter, was also not different in S1P2−/− mice under baseline or stimulated conditions. In vivo analysis of vascular function by flowmetry revealed decreases in mesenteric and renal resistance in S1P2−/− mice, especially during vasoconstriction with phenylephrine. In intact aortic rings, the concentration-force relations for both KCl and phenylephrine were right shifted in S1P2−/− mice, whereas the maximal isometric forces were not different. By contrast, in deendothelialized rings the concentration-force relations were not different but the maximal force was significantly greater in S1P2−/− aorta. Histologically, there were no apparent differences in vascular morphology. These data suggest that the S1P2 receptor plays an important role in the function of the vasculature and is an important mediator of normal hemodynamics. This is mediated, at least in part, through an effect on the endothelium, but direct effects on vascular smooth muscle cannot be ruled out and require further investigation.

scholarly journals Altered hippocampal arteriole structure and function in a rat model of preeclampsia: Potential role in impaired seizure-induced hyperemia

2016 ◽  
Vol 37 (8) ◽  
pp. 2857-2869 ◽  
Author(s):  
Abbie C Johnson ◽  
Marilyn J Cipolla
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Capillary Density ◽  
Nitric Oxide Donor ◽  
High Cholesterol Diet ◽  
Sprague Dawley ◽  
Capillary Rarefaction ◽  
And Function

We investigated the effect of experimental preeclampsia on hyperemia during seizure in the hippocampus and vascular function and structure of hippocampal arterioles using Sprague Dawley rats (n = 14/group) that were nonpregnant, pregnant (d20), or had experimental preeclampsia (induced by a high cholesterol diet d7–20). Hyperemia was measured via hydrogen clearance basally and during pentylenetetrazol-induced seizure (40–130 mg/kg i.v.). Reactivity of isolated and pressurized hippocampal arterioles to KCl, nitric oxide synthase inhibition with NG-nitro-L-arginine methyl ester and the nitric oxide donor sodium nitroprusside were investigated. Capillary density was quantified via immunohistochemistry. Cerebral blood flow increased during seizure vs. baseline in pregnant (118 ± 14 vs. 87 ± 9 mL/100 g/min; p < 0.05) and nonpregnant rats (106 ± 9 vs. 82 ± 9 mL/100 g/min; p < 0.05) but was unchanged in preeclamptic rats (79 ± 16 vs. 91 ± 4 mL/100 g/min; p > 0.05), suggesting impaired seizure-induced hyperemia in preeclampsia. Hippocampal arterioles from preeclamptic rats had less basal tone, and dilated less to 15 mM KCl (9 ± 8%) vs. pregnant (61 ± 27%) and nonpregnant rats (20 ± 11%). L-NAME had no effect on hippocampal arterioles in any group, but dilation to sodium nitroprusside was similar. Structurally, hippocampal arterioles from preeclamptic rats underwent inward hypotrophic remodeling and capillary rarefaction. Impaired seizure-induced hyperemia, vascular dysfunction, and limited vasodilatory reserve of hippocampal arterioles could potentiate hippocampal injury in preeclampsia especially during eclampsia.

scholarly journals Exploring the Association between Vascular Dysfunction and Skeletal Muscle Mass, Strength and Function in Healthy Adults: A Systematic Review

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 715 ◽  
Author(s):  
Svyatoslav Dvoretskiy ◽  
Jacqueline C. Lieblein-Boff ◽  
Satya Jonnalagadda ◽  
Philip J. Atherton ◽  
Bethan E. Phillips ◽  
...  
Keyword(s):  
Systematic Review ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Healthy Adults ◽  
Exercise Interventions ◽  
Randomized Controlled Studies ◽  
Muscle Health ◽  
And Function

Background: The prevalence of vascular dysfunction increases with advancing age, as does the loss of muscle mass, strength and function. This systematic review explores the association between vascular dysfunction and skeletal muscle health in healthy adults. Methods: EMBASE and MEDLINE were searched for cross-sectional and randomized controlled studies between January 2009 and April 2019, with 33 out of 1246 studies included based on predefined criteria. Assessments of muscular health included muscle mass, strength and function. Macrovascular function assessment included arterial stiffness (pulse wave velocity or augmentation index), carotid intima-media thickness, and flow-mediated dilation. Microvascular health assessment included capillary density or microvascular flow (contrast enhanced ultrasound). Results: All 33 studies demonstrated a significant association between vascular function and skeletal muscle health. Significant negative associations were reported between vascular dysfunction and -muscle strength (10 studies); -mass (9 studies); and -function (5 studies). Nine studies reported positive correlations between muscle mass and microvascular health. Conclusions: Multiple studies have revealed an association between vascular status and skeletal muscle health in healthy adults. This review points to the importance of screening for muscle health in adults with vascular dysfunction with a view to initiating early nutrition and exercise interventions to ameliorate functional decline over time.

The influence of prenatal exercise and pre-eclampsia on maternal vascular function

2017 ◽  
Vol 131 (17) ◽  
pp. 2223-2240 ◽  
Author(s):  
Rachel J. Skow ◽  
Emily C. King ◽  
Craig D. Steinback ◽  
Margie H. Davenport
Keyword(s):  
Arterial Stiffness ◽  
Endothelial Function ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Healthy Pregnancy ◽  
Large Expansion ◽  
Maternal Exercise ◽  
And Function ◽  
Prenatal Exercise

During healthy pregnancy, the cardiovascular system undergoes diverse adaptations to support adequate transfer of oxygen and nutrients from mother to fetus. In order to accommodate the large expansion of blood volume and associated cardiac output, the structure, mechanics, and function of the arteries are altered. Specifically, in healthy pregnancy there is a remodeling of arteries (increased angiogenesis and vasodilation), a generalized reduction in arterial stiffness (increased compliance), and an enhanced endothelial function. The development of pregnancy complications, specifically pre-eclampsia, is associated with poor placentation (decreased angiogenesis), increased arterial stiffness, and vascular dysfunction (reduced endothelial function). Many of the positive adaptations that occur in healthy pregnancy are enhanced in response to chronic exercise. Specifically, placental angiogenesis and endothelial function have been shown to improve to a greater extent in women who are active during their pregnancy compared with those who are not. Prenatal exercise may be important in helping to reduce the risk of vascular dysfunction in pregnancy. However, our knowledge of the vascular adaptations resulting from maternal exercise is limited. This review highlights maternal vascular adaptations occurring during healthy pregnancy, and contrasts the vascular maladaptation associated with pre-eclampsia. Finally, we discuss the role of prenatal exercise on vascular function in the potential prevention of vascular complications associated with pre-eclampsia.

Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats

Diabetes ◽  
1997 ◽  
Vol 46 (1) ◽  
pp. 94-106 ◽  
Author(s):  
J. R. Nyengaard ◽  
K. Chang ◽  
S. Berhorst ◽  
K. M. Reiser ◽  
J. R. Williamson ◽  
...  
Keyword(s):  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Structure And Function ◽  
Renal Structure ◽  
And Function

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

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