scholarly journals A gap junction inhibitor, carbenoxolone, induces spatiotemporal dispersion of renal cortical perfusion and impairs autoregulation

2016 ◽  
Vol 311 (3) ◽  
pp. H582-H591 ◽  
Author(s):  
Nicholas Mitrou ◽  
Branko Braam ◽  
William A. Cupples
Keyword(s):  
Gap Junctions ◽  
Spatial Variation ◽  
Gap Junction ◽  
Laser Speckle ◽  
Tubuloglomerular Feedback ◽  
Spatial And Temporal Variation ◽  
Contrast Imaging ◽  
Renal Vasculature ◽  
Renal Autoregulation ◽  
Gap Junction Inhibitor

Renal autoregulation dynamics originating from the myogenic response (MR) and tubuloglomerular feedback (TGF) can synchronize over large regions of the kidney surface, likely through gap junction-mediated electrotonic conduction and reflecting distributed operation of autoregulation. We tested the hypotheses that inhibition of gap junctions reduces spatial synchronization of autoregulation dynamics, abrogates spatial and temporal smoothing of renal perfusion, and impairs renal autoregulation. In male Long-Evans rats, we infused the gap junction inhibitor carbenoxolone (CBX) or the related glycyrrhizic acid (GZA) that does not block gap junctions into the renal artery and monitored renal blood flow (RBF) and surface perfusion by laser speckle contrast imaging. Neither CBX nor GZA altered RBF or mean surface perfusion. CBX preferentially increased spatial and temporal variation in the distribution of surface perfusion, increased spatial variation in the operating frequencies of the MR and TGF, and reduced phase coherence of TGF and increased its dispersion. CBX, but not GZA, impaired dynamic and steady-state autoregulation. Separately, infusion of the Rho kinase inhibitor Y-27632 paralyzed smooth muscle, grossly impaired dynamic autoregulation, and monotonically increased spatial variation of surface perfusion. These data suggest CBX inhibited gap junction communication, which in turn reduced the ability of TGF to synchronize among groups of nephrons. The results indicate that impaired autoregulation resulted from degraded synchronization, rather than the reverse. We show that network behavior in the renal vasculature is necessary for effective RBF autoregulation.

scholarly journals Nephron blood flow dynamics measured by laser speckle contrast imaging

2011 ◽  
Vol 300 (2) ◽  
pp. F319-F329 ◽  
Author(s):  
Niels-Henrik Holstein-Rathlou ◽  
Olga V. Sosnovtseva ◽  
Alexey N. Pavlov ◽  
William A. Cupples ◽  
Charlotte Mehlin Sorensen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Signal Transmission ◽  
Experimental Studies ◽  
Flow Dynamics ◽  
Laser Speckle ◽  
Tubuloglomerular Feedback ◽  
Contrast Imaging ◽  
Laser Speckle Contrast Imaging ◽  
Speckle Contrast ◽  
Blood Flow Dynamics

Tubuloglomerular feedback (TGF) has an important role in autoregulation of renal blood flow and glomerular filtration rate (GFR). Because of the characteristics of signal transmission in the feedback loop, the TGF undergoes self-sustained oscillations in single-nephron blood flow, GFR, and tubular pressure and flow. Nephrons interact by exchanging electrical signals conducted electrotonically through cells of the vascular wall, leading to synchronization of the TGF-mediated oscillations. Experimental studies of these interactions have been limited to observations on two or at most three nephrons simultaneously. The interacting nephron fields are likely to be more extensive. We have turned to laser speckle contrast imaging to measure the blood flow dynamics of 50–100 nephrons simultaneously on the renal surface of anesthetized rats. We report the application of this method and describe analytic techniques for extracting the desired data and for examining them for evidence of nephron synchronization. Synchronized TGF oscillations were detected in pairs or triplets of nephrons. The amplitude and the frequency of the oscillations changed with time, as did the patterns of synchronization. Synchronization may take place among nephrons not immediately adjacent on the surface of the kidney.

scholarly journals Renal Autoregulation in Health and Disease

2015 ◽  
Vol 95 (2) ◽  
pp. 405-511 ◽  
Author(s):  
Mattias Carlström ◽  
Christopher S. Wilcox ◽  
William J. Arendshorst
Keyword(s):  
Intracellular Signaling ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Tubuloglomerular Feedback ◽  
Free Calcium ◽  
Myogenic Response ◽  
Renal Vasculature ◽  
Renal Autoregulation ◽  
Positive Balance ◽  
Health And Disease

Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80–180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca2+]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca2+]ioccurs predominantly by Ca2+influx through L-type voltage-operated Ca2+channels (VOCC). Increased [Ca2+]iactivates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca2+from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca2+sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

scholarly journals Inhibition of Gap Junctions Sensitizes Primary Glioblastoma Cells for Temozolomide

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 858 ◽  
Author(s):  
Anna-Laura Potthoff ◽  
Dieter Henrik Heiland ◽  
Bernd O. Evert ◽  
Filipe Rodrigues Almeida ◽  
Simon P. Behringer ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Glioblastoma Cells ◽  
Primary Glioblastoma ◽  
Blood Brain ◽  
Elevated Activity ◽  
Essential Contribution ◽  
Gap Junction Inhibitor

Gap junctions have recently been shown to interconnect glioblastoma cells to a multicellular syncytial network, thereby allowing intercellular communication over long distances as well as enabling glioblastoma cells to form routes for brain microinvasion. Against this backdrop gap junction-targeted therapies might provide for an essential contribution to isolate cancer cells within the brain, thus increasing the tumor cells’ vulnerability to the standard chemotherapeutic agent temozolomide. By utilizing INI-0602—a novel gap junction inhibitor optimized for crossing the blood brain barrier—in an oncological setting, the present study was aimed at evaluating the potential of gap junction-targeted therapy on primary human glioblastoma cell populations. Pharmacological inhibition of gap junctions profoundly sensitized primary glioblastoma cells to temozolomide-mediated cell death. On the molecular level, gap junction inhibition was associated with elevated activity of the JNK signaling pathway. With the use of a novel gap junction inhibitor capable of crossing the blood–brain barrier—thus constituting an auspicious drug for clinical applicability—these results may constitute a promising new therapeutic strategy in the field of current translational glioblastoma research.

scholarly journals Connexins and the kidney

2010 ◽  
Vol 298 (5) ◽  
pp. R1143-R1155 ◽  
Author(s):  
Fiona Hanner ◽  
Charlotte Mehlin Sorensen ◽  
Niels-Henrik Holstein-Rathlou ◽  
János Peti-Peterdi
Keyword(s):  
Gap Junctions ◽  
Purinergic Signaling ◽  
Renin Angiotensin System ◽  
Juxtaglomerular Apparatus ◽  
Tubuloglomerular Feedback ◽  
Current Evidence ◽  
Morphological Evidence ◽  
Renal Vasculature ◽  
Angiotensin System ◽  
Major Function

Connexins (Cxs) are widely-expressed proteins that form gap junctions in most organs, including the kidney. In the renal vasculature, Cx37, Cx40, Cx43, and Cx45 are expressed, with predominant expression of Cx40 in the endothelial cells and Cx45 in the vascular smooth muscle cells. In the tubules, there is morphological evidence for the presence of gap junction plaques only in the proximal tubules. In the distal nephron, Cx30, Cx30.3, and Cx37 are expressed, but it is not known whether they form gap junctions connecting neighboring cells or whether they primarily act as hemichannels. As in other systems, the major function of Cxs in the kidney appears to be intercellular communication, although they may also form hemichannels that allow cellular secretion of large signaling molecules. Renal Cxs facilitate vascular conduction, juxtaglomerular apparatus calcium signaling, and tubular purinergic signaling. Accordingly, current evidence points to roles for these Cxs in several important regulatory mechanisms in the kidney, including the renin angiotensin system, tubuloglomerular feedback, and salt and water reabsorption. At the systemic level, renal Cxs may help regulate blood pressure and may be involved in hypertension and diabetes.

Transient impairment of dynamic renal autoregulation in early diabetes mellitus in rats

2015 ◽  
Vol 309 (8) ◽  
pp. R892-R901 ◽  
Author(s):  
Nicholas Mitrou ◽  
Sidney Morrison ◽  
Paymon Mousavi ◽  
Branko Braam ◽  
William A. Cupples
Keyword(s):  
Diabetes Mellitus ◽  
Laser Speckle ◽  
Contrast Imaging ◽  
Early Diabetes ◽  
Renal Vasoconstriction ◽  
Renal Autoregulation ◽  
Spatial Properties ◽  
Conflicting Evidence ◽  
Transient Impairment

Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with NG-nitro-l-arginine methyl ester (l-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. l-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO-dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1.

Laser speckle contrast imaging reveals large-scale synchronization of cortical autoregulation dynamics influenced by nitric oxide

2015 ◽  
Vol 308 (7) ◽  
pp. F661-F670 ◽  
Author(s):  
Nicholas Mitrou ◽  
Christopher G. Scully ◽  
Branko Braam ◽  
Ki H. Chon ◽  
William A. Cupples
Keyword(s):  
Nitric Oxide ◽  
Radial Artery ◽  
Large Scale ◽  
Control Period ◽  
Laser Speckle ◽  
Field Of View ◽  
Tubuloglomerular Feedback ◽  
Contrast Imaging ◽  
Long Distance ◽  
Cluster Graph

Synchronization of tubuloglomerular feedback (TGF) dynamics in nephrons that share a cortical radial artery is well known. It is less clear whether synchronization extends beyond a single cortical radial artery or whether it extends to the myogenic response (MR). We used LSCI to examine cortical perfusion dynamics in isoflurane-anesthetized, male Long-Evans rats. Inhibition of nitric oxide synthases by Nω-nitro-l-arginine methyl ester (l-NAME) was used to alter perfusion dynamics. Phase coherence (PC) was determined between all possible pixel pairs in either the MR or TGF band (0.09–0.3 and 0.015–0.06 Hz, respectively). The field of view (≈4 × 5 mm) was segmented into synchronized clusters based on mutual PC. During the control period, the field of view was often contained within one cluster for both MR and TGF. PC was moderate for TGF and modest for MR, although significant in both. In both MR and TGF, PC exhibited little spatial variation. After l-NAME, the number of clusters increased in both MR and TGF. MR clusters became more strongly synchronized while TGF clusters showed small highly coupled, high-PC regions that were coupled with low PC to the remainder of the cluster. Graph theory analysis probed modularity of synchronization. It confirmed weak synchronization of MR during control that probably was not physiologically relevant. It confirmed extensive and long-distance synchronization of TGF during control and showed increased modularity, albeit with larger modules seen in MR than in TGF after l-NAME. The results show widespread synchronization of MR and TGF that is differentially affected by nitric oxide.

scholarly journals Laser speckle contrast imaging for perfusion monitoring during surgical reconstruction of anorectal malformations

2021 ◽  
Vol 66 ◽  
pp. 101793
Author(s):  
Pernilla Stenström ◽  
Rafi Sheikh ◽  
Kristine Hagelsteen ◽  
Johanna Wennström Berggren ◽  
Malin Malmsjö
Keyword(s):  
Anorectal Malformations ◽  
Laser Speckle ◽  
Surgical Reconstruction ◽  
Contrast Imaging ◽  
Laser Speckle Contrast Imaging ◽  
Speckle Contrast

scholarly journals Spatial and Temporal Variation in Microbial Diversity and Community Structure in a Contaminated Mangrove Wetland

2020 ◽  
Vol 10 (17) ◽  
pp. 5850
Author(s):  
Jiaojiao Ma ◽  
Ting Zhou ◽  
Chunyu Xu ◽  
Dawen Shen ◽  
Songjun Xu ◽  
...  
Keyword(s):  
Community Structure ◽  
Spatial Variation ◽  
Temporal Variation ◽  
Bacterial Diversity ◽  
Diversity Index ◽  
Total Carbon ◽  
Spatial And Temporal Variation ◽  
Rrna Gene ◽  
Mangrove Wetland ◽  
Mangrove Soils

Field and laboratory investigations were conducted to characterize bacterial diversity and community structure in a badly contaminated mangrove wetland adjacent to the metropolitan area of a megacity in subtropical China. Next-generation sequencing technique was used for sequencing the V4–V5 region of the 16s rRNA gene on the Illumina system. Collectively, Proteobacteria, Chloroflexi, Planctomycetes, Actinobacteria and Bacteroidetes were the predominant phyla identified in the investigated soils. A significant spatial variation in bacterial diversity and community structure was observed for the investigated mangrove soils. Heavy metal pollution played a key role in reducing the bacterial diversity. The spatial variation in soil-borne heavy metals shaped the spatial variation in bacterial diversity and community structure in the study area. Other environmental factors such as total carbon and total nitrogen in the soils that are affected by seasonal change in temperature could also influence the bacterial abundance, diversity and community structure though the temporal variation was relatively weaker, as compared to spatial variation. The bacterial diversity index was lower in the investigated site than in the comparable reference site with less contaminated status. The community structure in mangrove soils at the current study site was, to a remarkable extent, different from those in the tropical mangrove wetlands around the world.

scholarly journals Preoperative endothelial dysfunction in cutaneous microcirculation is associated with postoperative organ injury after cardiac surgery using extracorporeal circulation: a prospective cohort study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stanislas Abrard ◽  
Olivier Fouquet ◽  
Jérémie Riou ◽  
Emmanuel Rineau ◽  
Pierre Abraham ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cohort Study ◽  
Endothelial Dysfunction ◽  
Postoperative Complications ◽  
Sofa Score ◽  
Primary Objective ◽  
Laser Speckle ◽  
Organ Injury ◽  
Contrast Imaging ◽  
The Relationship

Abstract Background Cardiac surgery is known to induce acute endothelial dysfunction, which may be central to the pathophysiology of postoperative complications. Preoperative endothelial dysfunction could also be implicated in the pathophysiology of postoperative complications after cardiac surgery. However, the relationship between preoperative endothelial function and postoperative outcomes remains unknown. The primary objective was to describe the relationship between a preoperative microcirculatory dysfunction identified by iontophoresis of acetylcholine (ACh), and postoperative organ injury in patients scheduled for cardiac surgery using cardiopulmonary bypass (CPB). Methods Sixty patients undergoing elective cardiac surgery using CPB were included in the analysis of a prospective, observational, single-center cohort study conducted from January to April 2019. Preoperative microcirculation was assessed with reactivity tests on the forearm (iontophoresis of ACh and nitroprusside). Skin blood flow was measured by laser speckle contrast imaging. Postoperative organ injury, the primary outcome, was defined as a Sequential Organ Failure Assessment score (SOFA) 48 h after surgery greater than 3. Results Organ injury at 48 h occurred in 29 cases (48.3%). Patients with postoperative organ injury (SOFA score > 3 at 48 h) had a longer time to reach the peak of preoperative iontophoresis of acetylcholine (133 s [104–156] vs 98 s [76–139] than patients without, P = 0.016), whereas endothelium-independent vasodilation to nitroprusside was similar in both groups. Beyond the proposed threshold of 105 s for time to reach the peak of preoperative endothelium-dependent vasodilation, three times more patients presented organ dysfunction at 48 h (76% vs 24% below or equal 105 s). In multivariable model, the time to reach the peak during iontophoresis of acetylcholine was an independent predictor of postoperative organ injury (odds ratio = 4.81, 95% confidence interval [1.16–19.94]; P = 0.030). Conclusions Patients who postoperatively developed organ injury (SOFA score > 3 at 48 h) had preoperatively a longer time to reach the peak of endothelium-dependent vasodilation. Trial registration Clinical-Trials.gov, NCT03631797. Registered 15 August 2018, https://clinicaltrials.gov/ct2/show/NCT03631797

scholarly journals Handheld versus mounted laser speckle contrast perfusion imaging demonstrated in psoriasis lesions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ata Chizari ◽  
Mirjam J. Schaap ◽  
Tom Knop ◽  
Yoeri E. Boink ◽  
Marieke M. B. Seyger ◽  
...  
Keyword(s):  
Perfusion Imaging ◽  
Laser Speckle ◽  
Psoriatic Skin ◽  
Post Processing ◽  
Speed Of Light ◽  
Contrast Imaging ◽  
Speckle Contrast ◽  
Frame Alignment ◽  
Wide Range ◽  
Perfusion Maps

AbstractEnabling handheld perfusion imaging would drastically improve the feasibility of perfusion imaging in clinical practice. Therefore, we examine the performance of handheld laser speckle contrast imaging (LSCI) measurements compared to mounted measurements, demonstrated in psoriatic skin. A pipeline is introduced to process, analyze and compare data of 11 measurement pairs (mounted-handheld LSCI modes) operated on 5 patients and various skin locations. The on-surface speeds (i.e. speed of light beam movements on the surface) are quantified employing mean separation (MS) segmentation and enhanced correlation coefficient maximization (ECC). The average on-surface speeds are found to be 8.5 times greater in handheld mode compared to mounted mode. Frame alignment sharpens temporally averaged perfusion maps, especially in the handheld case. The results show that after proper post-processing, the handheld measurements are in agreement with the corresponding mounted measurements on a visual basis. The absolute movement-induced difference between mounted-handheld pairs after the background correction is $$16.4\pm 9.3~\%$$ 16.4 ± 9.3 % (mean ± std, $$n=11$$ n = 11 ), with an absolute median difference of $$23.8\%$$ 23.8 % . Realization of handheld LSCI facilitates measurements on a wide range of skin areas bringing more convenience for both patients and medical staff.

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