RESUMO
BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.
Assuntos
Hipertensão Pulmonar , Imageamento Tridimensional , Camundongos Endogâmicos C57BL , Animais , Humanos , Camundongos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Masculino , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Microvasos/fisiopatologia , Microvasos/diagnóstico por imagem , Microvasos/patologia , Remodelação Vascular , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/patologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Função Ventricular Direita , Remodelação Ventricular , Modelos Animais de Doenças , Miócitos Cardíacos/patologiaRESUMO
Renal reserve capacity may be compromised following recovery from acute kidney injury (AKI) and could be used to identify impaired renal function in the face of restored glomerular filtration rate (GFR) or plasma creatinine. To investigate the loss of hemodynamic renal reserve responses following recovery in a model of AKI, rats were subjected to left unilateral renal ischemia-reperfusion (I/R) injury and contralateral nephrectomy and allowed to recover for 5 wk. Some rats were treated 24 h post-I/R by hydrodynamic isotonic fluid delivery (AKI-HIFD) of saline through the renal vein, previously shown to improve recovery and inflammation relative to control rats that received saline through the vena cava (AKI-VC). At 5 wk after surgery, plasma creatinine and GFR recovered to levels observed in uninephrectomized sham controls. Baseline renal blood flow (RBF) was not different between AKI or sham groups, but infusion of l-arginine (7.5 mg/kg/min) significantly increased RBF in sham controls, whereas the RBF response to l-arginine was significantly reduced in AKI-VC rats relative to sham rats (22.6 ± 2.2% vs. 13.8 ± 1.8%, P < 0.05). RBF responses were partially protected in AKI-HIFD rats relative to AKI-VC rats (17.0 ± 2.2%) and were not significantly different from sham rats. Capillary rarefaction observed in AKI-VC rats was significantly protected in AKI-HIFD rats. There was also a significant increase in T helper 17 cell infiltration and interstitial fibrosis in AKI-VC rats versus sham rats, which was not present in AKI-HIFD rats. These data suggest that recovery from AKI results in impaired hemodynamic reserve and that associated CKD progression may be mitigated by HIFD in the early post-AKI period.NEW & NOTEWORTHY Despite the apparent recovery of renal filtration function following acute kidney injury (AKI) in rats, the renal hemodynamic reserve response is significantly attenuated, suggesting that clinical evaluation of this parameter may provide information on the potential development of chronic kidney disease. Treatments such as hydrodynamic isotonic fluid delivery, or other treatments in the early post-AKI period, could minimize chronic inflammation or loss of microvessels with the potential to promote a more favorable outcome on long-term function.
Assuntos
Injúria Renal Aguda , Insuficiência Renal Crônica , Traumatismo por Reperfusão , Ratos , Animais , Hidrodinâmica , Creatinina , Ratos Sprague-Dawley , Rim , Injúria Renal Aguda/terapia , Hemodinâmica/fisiologia , Inflamação , Arginina , Modelos Animais de DoençasRESUMO
Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular morbidity and mortality. Capillary rarefaction may be both one of the causes as well as a consequence of CKD and cardiovascular disease. We reviewed the published literature on human biopsy studies and conclude that renal capillary rarefaction occurs independently of the cause of renal function decline. Moreover, glomerular hypertrophy may be an early sign of generalized endothelial dysfunction, while peritubular capillary loss occurs in advanced renal disease. Recent studies with non-invasive measurements show that capillary rarefaction is detected systemically (e.g., in the skin) in individuals with albuminuria, as sign of early CKD and/or generalized endothelial dysfunction. Decreased capillary density is found in omental fat, muscle and heart biopsies of patients with advanced CKD as well as in skin, fat, muscle, brain and heart biopsies of individuals with cardiovascular risk factors. No biopsy studies have yet been performed on capillary rarefaction in individuals with early CKD. At present it is unknown whether individuals with CKD and cardiovascular disease merely share the same risk factors for capillary rarefaction, or whether there is a causal relationship between rarefaction in renal and systemic capillaries. Further studies on renal and systemic capillary rarefaction, including their temporal relationship and underlying mechanisms are needed. This review stresses the importance of preserving and maintaining capillary integrity and homeostasis in the prevention and management of renal and cardiovascular disease.
Assuntos
Doenças Cardiovasculares , Rarefação Microvascular , Insuficiência Renal Crônica , Doenças Vasculares , Humanos , Capilares/patologia , Doenças Cardiovasculares/patologia , Rarefação Microvascular/patologia , Rim/patologia , Insuficiência Renal Crônica/patologia , Doenças Vasculares/patologiaRESUMO
BACKGROUND: Elevated mortality rates in patients with metabolic syndrome (MetS) are partly due to adverse remodeling of multiple organs, which may lead to cardiovascular disease, nonalcoholic fatty liver disease, kidney failure, or other conditions. MetS symptoms, such as obesity, hypertension, hyperglycemia, dyslipidemia, associated with insulin and leptin resistance, are recognized as major cardiovascular risk factors that adversely affect the heart. SUMMARY: Pathological cardiac remodeling is accompanied by endothelial cell dysfunction which may result in diminished coronary flow, dysregulated oxygen demand/supply balance, as well as vessel rarefaction. The reduced number of vessels and delayed or inhibited formation of collaterals after myocardial infarction in MetS heart may be due to unfavorable changes in endothelial cell metabolism but also to altered expression of vascular endothelial growth factor molecules, their receptors, and changes in signal transduction from the cell membrane, which severely affect angiogenesis. KEY MESSAGES: Given the established role of cardiac vessel endothelial cells in maintaining tissue homeostasis, defining the molecular background underlying vessel dysfunction associated with impaired angiogenesis is of great importance for future therapeutic purposes. Therefore, the aim of this paper was to present current information regarding vascular endothelial growth factor signaling in the myocardium of MetS individuals.
Assuntos
Vasos Coronários , Síndrome Metabólica , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular , Humanos , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/patologia , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Vasos Coronários/patologia , Remodelação Vascular , Neovascularização Fisiológica , Remodelação Ventricular , Rarefação Microvascular/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologiaRESUMO
Compared to non-urban environments, cities host ecological communities with altered taxonomic diversity and functional trait composition. However, we know little about how these urban changes take shape over time. Using historical bee (Apoidea: Anthophila) museum specimens supplemented with online repositories and researcher collections, we investigated whether bee species richness tracked urban and human population growth over the past 118 years. We also determined which species were no longer collected, whether those species shared certain traits, and if collector behavior changed over time. We focused on Wake County, North Carolina, United States where human population size has increased over 16 times over the last century along with the urban area within its largest city, Raleigh, which has increased over four times. We estimated bee species richness with occupancy models, and rarefaction and extrapolation curves to account for imperfect detection and sample coverage. To determine if bee traits correlated with when species were collected, we compiled information on native status, nesting habits, diet breadth, and sociality. We used non-metric multidimensional scaling to determine if individual collectors contributed different bee assemblages over time. In total, there were 328 species collected in Wake County. We found that although bee species richness varied, there was no clear trend in bee species richness over time. However, recent collections (since 2003) were missing 195 species, and there was a shift in trait composition, particularly lost species were below-ground nesters. The top collectors in the dataset differed in how often they collected bee species, but this was not consistent between historic and contemporary time periods; some contemporary collectors grouped closer together than others, potentially due to focusing on urban habitats. Use of historical collections and complimentary analyses can fill knowledge gaps to help understand temporal patterns of species richness in taxonomic groups that may not have planned long-term data.
Assuntos
Biodiversidade , Ecossistema , Animais , Abelhas , Estados Unidos , Humanos , Cidades , North Carolina , Densidade DemográficaRESUMO
Fungal spores are common airborne allergens, and fungal richness has been implicated in allergic disease. Amplicon sequencing of environmental DNA from air samples is a promising method to estimate fungal spore richness with semi-quantification of hundreds of taxa and can be combined with quantitative PCR to derive abundance estimates. However, it remains unclear how the choice of air sampling method influences these estimates. This study compared active sampling with a portable impactor and passive sampling with a passive trap over different durations to estimate fungal spore richness and the abundance of allergenic taxa. Air sampling was conducted indoors and outdoors at 12 residences, including repeated measurements with a portable impactor and passive traps with 1-day and 7-day durations. ITS2 amplicon sequence data were transformed to spore equivalents estimated by quantitative PCR, repeated active samples were combined, and abundance-based rarefaction was performed to standardize sample coverage for estimation of genus-level richness and spore abundance. Rarefied fungal richness was similar between methods indoors but higher for passive traps with a 7-day duration outdoors. Rarefied abundance of allergenic genera was similar between methods but some genera had lower abundance for passive traps with a 1-day duration, which differed indoors and outdoors indicating stochasticity in the collection of spores on collocated samplers. This study found that similar estimates of fungal spore richness and abundance of allergenic taxa can be obtained using a portable impactor or a passive trap within one day and that increased passive sample duration provides limited additional information.
Assuntos
Alérgenos , Fungos , Esporos Fúngicos/genética , Fungos/genética , Microbiologia do Ar , Monitoramento AmbientalRESUMO
Vascular endothelial growth factor (VEGF) and its cognate receptor (VEGFR2) system are crucial for cell functions associated with angiogenesis and vasculogenesis. Klotho contributes to vascular health maintenance in the kidney and other organs in mammals, but it is unknown whether renoprotection by Klotho is dependent on VEGF/VEGFR2 signaling. We used heterozygous VEGFR2-haploinsufficient (VEGFR2+/-) mice resulting from heterozygous knockin of green fluorescent protein in the locus of fetal liver kinase 1 encoding VEGFR2 to test the interplay of Klotho, phosphate, and VEGFR2 in kidney function, the vasculature, and fibrosis. VEGFR2+/- mice displayed downregulated VEGF/VEGFR2 signaling in the kidney, lower density of peritubular capillaries, and accelerated kidney fibrosis, all of which were also found in the homozygous Klotho hypomorphic mice. High dietary phosphate induced higher plasma phosphate, greater peritubular capillary rarefaction, and more kidney fibrosis in VEGFR2+/- mice compared with wild-type mice. Genetic overexpression of Klotho significantly attenuated the elevated plasma phosphate, kidney dysfunction, peritubular capillary rarefaction, and kidney fibrosis induced by a high-phosphate diet in wild-type mice but only modestly ameliorated these changes in the VEGFR2+/- background. In cultured endothelial cells, VEGFR2 inhibition reduced free VEGFR2 but enhanced its costaining of an endothelial marker (CD31) and exacerbated phosphotoxicity. Klotho protein maintained VEGFR2 expression and attenuated high phosphate-induced cell injury, which was reduced by VEGFR2 inhibition. In conclusion, normal VEGFR2 function is required for vascular integrity and for Klotho to exert vascular protective and antifibrotic actions in the kidney partially through the regulation of VEGFR2 function.NEW & NOTEWORTHY This research paper studied the interplay of vascular endothelial growth factor receptor type 2 (VEGFR2), high dietary phosphate, and Klotho, an antiaging protein, in peritubular structure and kidney fibrosis. Klotho protein was shown to maintain VEGFR2 expression in the kidney and reduce high phosphate-induced cell injury. However, Klotho cytoprotection was attenuated by VEGFR2 inhibition. Thus, normal VEGFR2 function is required for vascular integrity and Klotho to exert vascular protective and antifibrotic actions in the kidney.
Assuntos
Citoproteção , Nefropatias , Rim , Proteínas Klotho , Rarefação Microvascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Camundongos , Células Endoteliais/metabolismo , Fibrose , Rim/irrigação sanguínea , Rim/patologia , Nefropatias/patologia , Rarefação Microvascular/patologia , Fosfatos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/deficiência , Proteínas Klotho/genética , Proteínas Klotho/metabolismoRESUMO
Wild animals have been implicated as reservoirs and even "melting pots" of pathogenic and antimicrobial-resistant bacteria of concern to human health. Though Escherichia coli is common among vertebrate guts and plays a role in the propagation of such genetic information, few studies have explored its diversity beyond humans nor the ecological factors that influence its diversity and distribution in wild animals. We characterized an average of 20 E. coli isolates per scat sample (n = 84) from a community of 14 wild and 3 domestic species. The phylogeny of E. coli comprises 8 phylogroups that are differentially associated with pathogenicity and antibiotic resistance, and we uncovered all of them in one small biological preserve surrounded by intense human activity. Challenging previous assumptions that a single isolate is representative of within-host phylogroup diversity, 57% of individual animals sampled carried multiple phylogroups simultaneously. Host species' phylogroup richness saturated at different levels across species and encapsulated vast within-sample and within-species variation, indicating that distribution patterns are influenced both by isolation source and laboratory sampling depth. Using ecological methods that ensure statistical relevance, we identify trends in phylogroup prevalence associated with host and environmental factors. The vast genetic diversity and broad distribution of E. coli in wildlife populations has implications for biodiversity conservation, agriculture, and public health, as well as for gauging unknown risks at the urban-wildland interface. We propose critical directions for future studies of the "wild side" of E. coli that will expand our understanding of its ecology and evolution beyond the human environment. IMPORTANCE To our knowledge, neither the phylogroup diversity of E. coli within individual wild animals nor that within an interacting multispecies community have previously been assessed. In doing so, we uncovered the globally known phylogroup diversity from an animal community on a preserve imbedded in a human-dominated landscape. We revealed that the phylogroup composition in domestic animals differed greatly from that in their wild counterparts, implying potential human impacts on the domestic animal gut. Significantly, many wild individuals hosted multiple phylogroups simultaneously, indicating the potential for strain-mixing and zoonotic spillback, especially as human encroachment into wildlands increases in the Anthropocene. We reason that due to extensive anthropogenic environmental contamination, wildlife is increasingly exposed to our waste, including E. coli and antibiotics. The gaps in the ecological and evolutionary understanding of E. coli thus necessitate a significant uptick in research to better understand human impacts on wildlife and the risk for zoonotic pathogen emergence.
Assuntos
Infecções por Escherichia coli , Escherichia coli , Animais , Humanos , Infecções por Escherichia coli/microbiologia , Animais Domésticos/microbiologia , Animais Selvagens/microbiologia , Virulência , FilogeniaRESUMO
PURPOSE OF REVIEW: This review aims to explore the role of microvascular dysfunction in obesity-hypertension, discuss the effects obesity has on renal microvasculature, review the current methods for assessing microvascular dysfunction and available therapeutic options, and identify critical areas for further research. RECENT FINDINGS: There is a strong association between obesity and hypertension. However, the pathophysiology of obesity-hypertension is not clear. Microvascular dysfunction has been linked to hypertension and obesity and could be an important mediator of obesity-related hypertension. Newer therapies for hypertension and obesity could have ameliorating effects on microvascular dysfunction, including GLP-1 agonists and SGLT-2 inhibitors. There is still much progress to be made in our understanding of the complex interplay between obesity, hypertension, and microvascular dysfunction. Continued efforts to understand microvascular dysfunction and its role in obesity-hypertension are crucial to develop precision therapy to target obesity-hypertension.
Assuntos
Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Obesidade/complicações , RimRESUMO
PURPOSE OF REVIEW: To review current literature examining the presence of subclinical micro- and macrovascular alterations in normotensive individuals and their clinical significance in terms of hypertension prediction. Emphasis is placed on alterations that can be detected in peripheral vascular beds using non-invasive, easily applicable methodology, as these are in general easier to capture and evaluate in clinical practice compared to more complex invasive or functional tests. RECENT FINDINGS: Arterial stiffness, increased carotid intima-media thickness, and altered retinal microvascular diameters predict the progression from the normotensive to the hypertensive state. By contrast, there is substantial lack of relevant prospective studies for skin microvascular alterations. Although conclusions regarding causality cannot be safely deduced from available studies, detection of morphological and functional vascular alterations in normotensive individuals emerges as a sensitive indicator of progression to hypertension and hence increased CVD risk. An increasing amount of evidence suggests that early detection of subclinical micro- and macrovascular alterations would be clinically useful for the early identification of individuals at high risk for future hypertension onset. Methodological issues and gaps in knowledge need to be addressed before detection of such changes could guide the development of strategies to prevent new-onset hypertension in normotensive individuals.
Assuntos
Hipertensão , Rigidez Vascular , Humanos , Hipertensão/diagnóstico , Espessura Intima-Media Carotídea , Relevância Clínica , Estudos Prospectivos , Pressão SanguíneaRESUMO
Perivascular spaces (PVS) and their enlargement (EPVS) have been gaining interest as EPVS can be visualized non-invasively by magnetic resonance imaging (MRI) when viewing T-2-weighted images. EPVS are most commonly observed in the regions of the basal ganglia and the centrum semiovale; however, they have also been identified in the frontal cortex and hippocampal regions. EPVS are known to be increased in aging and hypertension, and are considered to be a biomarker of cerebral small vessel disease (SVD). Interest in EPVS has been significantly increased because these PVS are now considered to be an essential conduit necessary for the glymphatic pathway to provide the necessary efflux of metabolic waste. Metabolic waste includes misfolded proteins of amyloid beta and tau that are known to accumulate in late-onset Alzheimer's disease (LOAD) within the interstitial fluid that is delivered to the subarachnoid space and eventually the cerebral spinal fluid (CSF). The CSF acts as a sink for accumulating neurotoxicities and allows clinical screening to potentially detect if LOAD may be developing early on in its clinical progression via spinal fluid examination. EPVS are thought to occur by obstruction of the PVS that associates with excessive neuroinflammation, oxidative stress, and vascular stiffening that impairs flow due to a dampening of the arterial and arteriolar pulsatility that aids in the convective flow of the metabolic debris within the glymphatic effluxing system. Additionally, increased EPVS has also been associated with Parkinson's disease and non-age-related multiple sclerosis (MS).
Assuntos
Peptídeos beta-Amiloides , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Envelhecimento , Gânglios da Base/patologia , ArtériasRESUMO
Fibrosis, characterized by abnormal and excessive deposition of extracellular matrix, results in compromised tissue and organ structure. This can lead to reduced organ function and eventual failure. Although activated fibroblasts, called myofibroblasts, are considered the central players in fibrosis, the contribution of endothelial cells to the inception and progression of fibrosis has become increasingly recognized. Endothelial cells can contribute to fibrosis by acting as a source of myofibroblasts via endothelial-mesenchymal transition (EndoMT), or by becoming senescent, by secretion of profibrotic mediators and pro-inflammatory cytokines, chemokines and exosomes, promoting the recruitment of immune cells, and by participating in vascular rarefaction and decreased angiogenesis. In this review, we provide an overview of the different aspects of fibrosis in which endothelial cells have been implicated.
Assuntos
Células Endoteliais/metabolismo , Fibrose/metabolismo , Animais , Células Endoteliais/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Fibrose/patologia , HumanosRESUMO
Applications of genetic-based estimates of population size are expanding, especially for species for which traditional demographic estimation methods are intractable due to the rarity of adult encounters. Estimates of breeding population size (NS ) are particularly amenable to genetic-based approaches as the parameter can be estimated using pedigrees reconstructed from genetic data gathered from discrete juvenile cohorts, therefore eliminating the need to sample adults in the population. However, a critical evaluation of how genotyping and sampling effort influence bias in pedigree reconstruction, and how these biases subsequently influence estimates of NS , is needed to evaluate the efficacy of the approach under a range of scenarios. We simulated a model system to understand the interactive effects of genotyping and sampling effort on error in genetic pedigrees reconstructed from the program COLONY. We then evaluated how errors in pedigree reconstruction influenced bias and precision in estimates of NS using three different rarefaction estimators. Results indicated that pedigree error can be minimal when adequate genetic data are available, such as when juvenile sample sizes are large and/or individuals are genotyped at many informative loci. However, even in cases for which data are limited, using results of the simulation analysis to understand the magnitude and sources of bias in reconstructed pedigrees can still be informative when estimating NS . We applied results of the simulation analysis to evaluate N Ì $$ \hat{N} $$ S for a population of federally endangered Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) in the Delaware River, USA. Our results indicated that NS is likely to be three orders of magnitude lower compared with historic breeding population sizes, which is a considerable advancement in our understanding of the population status of Atlantic sturgeon in the Delaware River. Our analyses are broadly applicable in the design and interpretation of studies seeking to estimate NS and can help to guide conservation decisions when ecological uncertainty is high. The utility of these results is expected to grow as rapid advances in genetic technologies increase the popularity of genetic population monitoring and estimation.
Assuntos
Cruzamento , Genética Populacional , Animais , Viés , Peixes/genética , Humanos , Linhagem , Densidade DemográficaRESUMO
Health and disease risk in the adulthood are known to be affected by the early developmental environment. Kidney diseases are one of these diseases, and kidneys are altered both structurally and functionally by adverse pre- and perinatal events. The most known structural change is low nephron number seen in subjects born low birth weight and/or preterm. In various animal models of intrauterine growth restriction (IUGR), one of the causes of low birth weight, the mechanism of low nephron number was investigated. While apoptosis of metanephric mesenchyme has been suggested to be the cause, I showed that suppression of ureteric branching, global DNA methylation, and caspase-3 activity also contributes to the mechanism. Other structural changes caused by adverse fetal and neonatal environments include peritubular and glomerular capillary rarefaction and low podocyte endowment. These are aggravated by postnatal development of focal glomerulosclerosis and tubulointerstitial fibrosis that result from low nephron number. Functional changes can be seen in tubules, endothelium, renin-angiotensin system, sympathetic nervous system, oxidative stress, and others. As an example, I reported that aggravated nitrosative stress in a rat IUGR model resulted in more severe tubular necrosis and tubulointerstitial fibrosis after unilateral ureteral obstruction. The mechanism of various functional changes needs to be clarified but may be explained by epigenetic modifications.
Assuntos
Nefropatias , Podócitos , Adulto , Animais , Feminino , Retardo do Crescimento Fetal , Humanos , Rim , Glomérulos Renais , Gravidez , RatosRESUMO
Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-ß: transforming growth factor-ß; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response.
Assuntos
Rarefação Microvascular , Insuficiência Renal Crônica , Animais , Fibrose , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico , Guanilil Ciclase Solúvel , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio VascularRESUMO
Manure-inhabiting Mesostigmata mites are important biological control agents of pest flies. However, the biodiversity of this mite community is mainly known from Europe and America, and especially from cattle manure. This study examined the diversity and abundance of Mesostigmata mites associated with various types of manure in an (intensive) agricultural region of the Middle East, i.e., the city Ahvaz and its suburbs, in southwest Iran. Mite samples were extracted from manure of cattle, buffalo, sheep, horse, poultry and quail in 30 livestock and poultry farms. In total, 40 species belonging to 24 genera and 16 families were identified. The most diverse families were Laelapidae with eight species, Macrochelidae with seven and Parasitidae with six. Macrocheles muscaedomesticae and Uroobovella marginata were the most widespread species, recorded in 28 and 27 out of 30 collection sites, respectively. Two species, M. sumbaensis and U. marginata, were found in all studied manures. Simpson's diversity index recorded the highest diversity in buffalo and sheep manure. Real and theoretical species richness (rarefaction curves) were congruent in number of individuals. The presence of seven species of Macrochelidae in the manure confirms that these are important predators of the house fly for the region of Ahvaz and its suburbs. Members of the Parasitidae were highly prevalent, with one species known as a specialized predator of house fly eggs. This work aims to encourage further studies on the diversity of Mesostigmata in these agricultural settings, and further continue assessing the feasibility of these mites as effective biocontrol agents of filth flies in different types of manure and from different corners of the world.
Assuntos
Moscas Domésticas , Ácaros , Animais , Bovinos , Cavalos , Humanos , Irã (Geográfico) , Esterco , Aves Domésticas , OvinosRESUMO
Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Caspase-3, an effector responsible for apoptosis execution, is activated within the peritubular capillary (PTC) in the early stage of IRI-induced acute kidney injury (AKI). Recently, we showed that caspase-3-dependent microvascular rarefaction plays a key role in fibrosis development after mild renal IRI. Here, we further characterized the role of caspase-3 in microvascular dysfunction and progressive renal failure in both mild and severe AKI, by performing unilateral renal artery clamping for 30/60 min with contralateral nephrectomy in wild-type (C57BL/6) or caspase-3-/- mice. In both forms of AKI, caspase-3-/- mice showed better long-term outcomes despite worse initial tubular injury. After 3 wk, they showed reduced PTC injury, decreased PTC collagen deposition and α-smooth muscle actin expression, and lower tubular injury scores compared with wild-type animals. Caspase-3-/- mice with severe IRI also showed better preservation of long-term renal function. Intravital imaging and microcomputed tomography revealed preserved PTC permeability and better terminal capillary density in caspase-3-/- mice. Collectively, these results demonstrate the pivotal importance of caspase-3 in regulating long-term renal function after IRI and establish the predominant role of PTC dysfunction as a major contributor to progressive renal dysfunction.NEW & NOTEWORTHY Our findings demonstrate the pivotal importance of caspase-3 in regulating renal microvascular dysfunction, fibrogenesis, and long-term renal impairment after acute kidney injury induced by ischemia-reperfusion injury. Furthermore, this study establishes the predominant role of peritubular capillary integrity as a major contributor to progressive renal dysfunction after ischemia-reperfusion injury.
Assuntos
Injúria Renal Aguda/metabolismo , Caspase 3/metabolismo , Insuficiência Renal Crônica/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Capilares/metabolismo , Feminino , Rim/metabolismo , Camundongos Endogâmicos C57BL , Rarefação Microvascular/patologia , Traumatismo por Reperfusão/patologiaRESUMO
OBJECTIVE: Endothelial dysfunction has been associated with increased cardiovascular events and overall mortality. Microvascular damage is prevalent both in diabetes mellitus (DM) and chronic kidney disease (CKD). Our aim was to compare microcirculatory function parameters in diabetic and non-diabetic CKD patients via nailfold video-capillaroscopy. METHODS: We included 48 diabetic and 48 non-diabetic adult CKD patients. All participants underwent nailfold video-capillaroscopy, during which capillary density was measured at normal conditions (baseline), after a 4-minute arterial occlusion (postocclusive reactive hyperemia), and at the end of a 2-minute venous occlusion (congestion phase). RESULTS: Diabetic patients presented significantly lower capillary density during reactive hyperemia (36.3 ± 3.8 vs 38.3 ± 4.3 capillaries/mm2 , P = .022) and at venous congestion (37.8 ± 4.0 vs 39.8 ± 4.2 capillaries/mm2 , P = .015). When stratified according to CKD stages, only in stage 3b capillary density was significantly lower in diabetic compared to non-diabetic subjects at baseline, during postocclusive hyperemia (36.8 ± 2.7 vs 40.0 ± 4.3 capillaries/mm2 , P = .037) and venous congestion (38.3 ± 2.8 vs 41.5 ± 3.5 capillaries/mm2 , P = .022). CONCLUSIONS: Capillary density during postocclusive hyperemia and after venous congestion is lower in diabetic compared to non-diabetic CKD patients, a finding indicative that diabetes is an additional factor contributing to microcirculatory structural and functional impairment in CKD. These differences are more prominent in CKD stage 3b.
Assuntos
Diabetes Mellitus , Hiperemia , Insuficiência Renal Crônica , Doenças Vasculares , Capilares , Humanos , Microcirculação , Angioscopia Microscópica , PeleRESUMO
Kidneys are highly vascular organs that despite their relatively small size receive 20% of the cardiac output. The highly intricate, delicately organized structure of renal microcirculation is essential to enable renal function and glomerular filtration rate through the local modulation of renal blood flow and intraglomerular pressure. Not surprisingly, the dysregulation of blood flow within the microvessels (abnormal vasoreactivity), fibrosis driven by disordered vascular-renal cross talk, or the loss of renal microvasculature (rarefaction) is associated with kidney disease. In addition, kidney disease can cause microcirculatory dysfunction in distant organs such as the heart and brain, mediated by mechanisms that remain to be elucidated. The objective of this review is to highlight the role of renal microvasculature in kidney disease. The overview will outline the impetus to study renal microvasculature, the bidirectional relationship between kidney disease and microvascular dysfunction, the key pathways driving microvascular diseases such as vasoreactivity, the cell dynamics coordinating fibrosis, and vessel rarefaction. Finally, we will also briefly highlight new therapies targeting the renal microvasculature to improve renal function.
Assuntos
Nefropatias , Microcirculação , Fibrose , Humanos , Rim/patologia , Nefropatias/patologia , Microvasos/patologiaRESUMO
Land-use change is a significant cause of anthropogenic extinctions, which are likely to continue and accelerate as habitat conversion proceeds in most biomes. One way to understand the effects of habitat loss on biodiversity is through improved tools for predicting the number and identity of species losses in response to habitat loss. There are relatively few methods for predicting extinctions and even fewer opportunities for rigorously assessing the quality of these predictions. In this paper, we address these issues by applying a new method based on rarefaction to predict species losses after random, but aggregated, habitat loss. We compare predictions from three rarefaction models, individual-based, sample-based, and spatially clustered, to those derived from a commonly used extinction estimation method, the species-area relationship (SAR). We apply each method to a mesocosm experiment, in which we aim to predict species richness and extinctions of arthropods immediately following 50% habitat loss. While each model produced strikingly accurate predictions of species richness immediately after the habitat loss disturbance, each model significantly underestimated the number of extinctions occurring at both the local (within-mesocosm) and regional (treatment-wide) scales. Despite the stochastic nature of our small-scale, short-term, and randomly applied habitat loss experiment, we found surprisingly clear evidence for extinction selectivity, for example, when abundant species with low extinction probabilities were extirpated following habitat loss. The important role played by selective extinction even in this contrived experimental system suggests that ecologically driven, trait-based extinctions play an equally important role to stochastic extinction, even when the disturbance itself has no clear selectivity. As a result, neutrally stochastic null models such as the SAR and rarefaction are likely to underestimate extinctions caused by habitat loss. Nevertheless, given the difficulty of predicting extinctions, null models provide useful benchmarks for conservation planning by providing minimum estimates and probabilities of species extinctions.