Prediction of Pre-Loading Relaxation of Bolt Structure of Complex Equipment under Tangential Cyclic Load.

Bolts have the advantages of simple installation and easy removal. They are widely applied in aerospace and high-speed railway traffic. However, the loosening of bolts under mixed loads can lead to nonlinear decreases in pre-loading. This affects the safety performance of the structure and may lead to catastrophic consequences. Existing techniques cannot be used to monitor the bolt performance status in time. This has caused significant problems with the safety and reliability of equipment. In order to study the relaxation law of bolt pre-loading, this paper carries out an experimental analysis for 8.8-grade hexagonal bolts and calibrates the torque coefficient. We also studied different loading waveforms, nickel steel plate surface roughnesses, tangential displacement frequencies, four different strengths and bolt head contact areas of the bolt, the initial pre-loading, and the effects of tangential cyclic displacement on pre-loading relaxation. This was done in order to accurately predict the degree of bolt pre-loading loosening under external loads. The laws are described using the allometric model function and the nine-stage polynomial function. The least squares method is used to identify the parameters in the function. The results show that bolts with a smooth surface of the connected structure nickel steel flat plate, high-frequency working conditions, half-sine wave, and a high-strength have better anti-loosening properties. Taking 5-10 cycles of cyclic loading as a boundary, the pre-loading relaxation is divided into two stages. The first stage is a stage of rapid decrease in bolt pre-loading, and the second stage is the slow decrease process. The performance prediction study shows that the allometric model function is the worst fitted, at 71.7% for the small displacement condition. Other than that, the allometric model function and the nine-stage polynomial function can predict more than 85.5% and 90.4%, which require the use of least squares to identify two and ten unknown parameters, respectively. The complexity of the two is different, but both can by better indicators than the pre-loading relaxation law under specific conditions. It helps to improve the monitoring of bolt loosening and the system use cycle, and it can provide theoretical support for complex equipment working for a long time.

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI.

Introduction: Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1ß (IL-1ß) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI. Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre + /IL-1R1 fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre - /IL-1R1 fl/fl-Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice. Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1ß) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1ß-induced tubular cell injury. Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

A new modular framework for high-level application development at HEPS.

As a representative of the fourth-generation light sources, the High Energy Photon Source (HEPS) in Beijing, China, utilizes a multi-bend achromat lattice to obtain an approximately 100 times emittance reduction compared with third-generation light sources. New technologies bring new challenges to operate the storage ring. In order to meet the beam commissioning requirements of HEPS, a new framework for the development of high-level applications (HLAs) has been created. The key part of the new framework is a dual-layer physical module to facilitate the seamless fusion of physical simulation models with the real machine, allowing for fast switching between different simulation models to accommodate the various simulation scenarios. As a framework designed for development of physical applications, all variables are based on physical quantities. This allows physicists to analytically assess measurement parameters and optimize machine parameters in a more intuitive manner. To enhance both extensibility and adaptability, a modular design strategy is utilized, partitioning the entire framework into discrete modules in alignment with the requirements of HLA development. This strategy not only facilitates the independent development of each module but also minimizes inter-module coupling, thereby simplifying the maintenance and expansion of the entire framework. To simplify the development complexity, the design of the new framework is implemented using Python and is called Python-based Accelerator Physics Application Set (Pyapas). Taking advantage of Python's flexibility and robust library support, we are able to develop and iterate quickly, while also allowing for seamless integration with other scientific computing applications. HLAs for both the HEPS linac and booster have been successfully developed. During the beam commissioning process at the linac, Pyapas's ease of use and reliability have significantly reduced the time required for the beam commissioning operators. As a development framework for HLA designed for the new-generation light sources, Pyapas has the versatility to be employed with HEPS, as well as with other comparable light sources, due to its adaptability.

Confidence in dementia care and care approach toward dementia among the nursing staff in long-term care facilities in China: a cross-sectional survey.

Background: Confidence and appropriate care approach toward dementia among nursing staff (nurses and care assistants) are crucial manifestations of competency to deal with the complexity of dementia care in long-term care facilities (LTCFs). The purpose of this study was to investigate the confidence in dementia care and care approach among nursing staff in LTCFs in mainland China. Methods: A cross-sectional study design was utilized in LTCFs in Shandong Province, mainland China. A convenient sample included of 317 nursing staff drawn from 15 LTCFs. Survey questions included (a) demographics, (b) dementia knowledge, (c) dementia care confidence, and (d) approach to care for people with dementia. Data were analyzed with descriptive statistics. Factors associated with confidence and care approach for people with dementia were examined using Pearson's correlation and multivariate regression analyses. Results: Dementia care confidence was generally moderate. Factors affecting confidence to care for people with dementia included educational level, months of caring dementia patients, and dementia knowledge. Most nursing staff did not use a person-centered care approach which was significantly associated with their age, dementia-learning experience, and knowledge and confidence toward caring for people with dementia. Conclusion: A positive correlation was identified between confidence to care for people with dementia and nursing staff care approach. Clinical recommendations are provided to further develop education strategies tailored for nursing staff to meet the growing demand for dementia care services.

Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI.

SIGNIFICANCE STATEMENT: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. BACKGROUND: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. METHODS: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. RESULTS: scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. CONCLUSIONS: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

Arsenopyrite dissolution in circumneutral oxic environments: The effect of pyrophosphate and dissolved Mn(III).

The oxidative dissolution of As from arsenopyrite, one important arsenic mineral in reducing conditions, poses an environmental hazard to natural aquatic systems. The dissolution of arsenopyrite occurs slowly due to the surface precipitates of iron oxides in circumneutral oxic environments. However, the presence of natural ligands and coexisting metals may change the release of Fe species, which would be of critical importance to the dissolution of arsenopyrite. Here, we investigated the oxidative dissolution of arsenopyrite induced by pyrophosphate (PP) and dissolved Mn(III) species as a natural occurring Mn species with strong complexation affinity to PP. With the presence of PP, the formation of Fe(II)-PP complexes and its rapid oxidation to dissolved Fe(III)-PP species resulted in a substantial increase in the generation of hydroxyl radicals (•OH) under ambient dark conditions, contributing to faster dissolution of arsenopyrite and higher percentage of As(V) in the dissolved products. Dissolved Mn(III), though considered as an extra oxidant besides oxygen, unexpectedly acted as a radical scavenger for •OH and inhibited the production of As(V). Moreover, the oxidation of sulfur species differed in the two systems as significant formation of thiosulfate was observed with the presence of PP, which did not occur in the system with dissolved Mn(III). Overall, the effects of dissolved Mn(III) and PP on the dissolution of arsenopyrite and the subsequent transformation of Fe, As and S species have important implications for disentangling the interactions among these metastable elements, and for assessing their transport and environmental impacts in aquatic systems.

A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.

The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80hi and CD11bhi cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80hi macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80hi macrophages would worsen septic AKI. F4/80hi macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1dtr/wt (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1dtr/wt (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80hi macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80hi macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.

Actions of Dendritic Cells in the Kidney during Hypertension.

The immune response plays a critical role in the pathogenesis of hypertension, and immune cell populations can promote blood pressure elevation via actions in the kidney. Among these cell lineages, dendritic cells (DCs), the most potent antigen-presenting cells, play a central role in regulating immune response during hypertension and kidney disease. DCs have different subtypes, and renal DCs are comprised of the CD103+ CD11b- and CD103- CD11b+ subsets. DCs become mature and express costimulatory molecules on their surface once they encounter antigen. Isolevuglandin-modified proteins function as antigens to activate DCs and trigger them to stimulate T cells. Activated T cells accumulate in the hypertensive kidney, release effector cytokines, promote renal oxidative stress, and promote renal salt and water retention. Individual subsets of activated T cells can secrete tumor necrosis factor-alpha, interleukin-17A, and interferon-gamma, each of which has augmented the elevation of blood pressure in hypertensive models by enhancing renal sodium transport. Fms-like tyrosine kinase 3 ligand-dependent classical DCs are required to sustain the full hypertensive response, but C-X3 -C chemokine receptor 1 positive DCs do not regulate blood pressure. Excess sodium enters the DC through transporters to activate DCs, whereas the ubiquitin editor A20 in dendritic cells constrains blood pressure elevation by limiting T cell activation. By contrast, activation of the salt sensing kinase, serum/glucocorticoid kinase 1 in DCs exacerbates salt-sensitive hypertension. This article discusses recent studies illustrating mechanisms through which DC-T cell interactions modulate levels of pro-hypertensive mediators to regulate blood pressure via actions in the kidney. © 2022 American Physiological Society. Compr Physiol 12:1-15, 2022.

The Immune System in Hypertension: a Lost Shaker of Salt 2021 Lewis K. Dahl Memorial Lecture.

The seminal observations of Dr Lewis Dahl regarding renal mechanisms of hypertension remain highly relevant in light of more recent experiments showing that immune system dysfunction contributes to hypertension pathogenesis. Dr Dahl established that inappropriate salt retention in the kidney plays a central role via Ohm's Law in permitting blood pressure elevation. Nevertheless, inflammatory cytokines whose expression is induced in the early stages of hypertension can alter renal blood flow and sodium transporter expression and activity to foster renal sodium retention. By elaborating these cytokines and reactive oxygen species, myeloid cells and T lymphocytes can connect systemic inflammatory signals to aberrant kidney functions that allow sustained hypertension. By activating T lymphocytes, antigen-presenting cells such as dendritic cells represent an afferent sensing mechanism triggering T cell activation, cytokine generation, and renal salt and water reabsorption. Manipulating these inflammatory signals to attenuate hypertension without causing prohibitive systemic immunosuppression will pose a challenge, but disrupting actions of inflammatory mediators locally within the kidney may offer a path through which to target immune-mediated mechanisms of hypertension while capitalizing on Dr Dahl's key recognition of the kidney's importance in blood pressure regulation.

Type 1 Angiotensin Receptors on CD11c-Expressing Cells Protect Against Hypertension by Regulating Dendritic Cell-Mediated T Cell Activation.

BACKGROUND: Type 1 angiotensin (AT1) receptors are expressed on immune cells, and we previously found that bone marrow-derived AT1 receptors protect against Ang (angiotensin) II-induced hypertension. CD11c is expressed on myeloid cells derived from the bone marrow, including dendritic cells (DCs) that activate T lymphocytes. Here, we examined the role of AT1 receptors on CD11c+ cells in hypertension pathogenesis. METHODS: Mice lacking the dominant murine AT1 receptor isoform, AT1a, on CD11c+ cells (dendritic cell [DC] AT1aR knockout [KO]) and wild-type (WT) littermates were subjected to Ang II-induced hypertension. Blood pressures were measured by radiotelemetry. RESULTS: DC AT1aR KO mice had exaggerated hypertensive responses to chronic Ang II infusion with enhanced renal accumulation of effector memory T cells and CD40+ DCs. CCL5 (C-C motif chemokine ligand 5) recruits T cells into injured tissues, and CCR7 (C-C motif chemokine receptor 7) facilitates DC and T cell interactions in the kidney lymph node to allow T cell activation. DCs from the hypertensive DC AT1aR KO kidneys expressed higher levels of CCL5 and CCR7. mRNA expressions for CCR7 and tumor necrosis factor-α were increased in CD4+ T cells from the renal lymph nodes of DC AT1aR KO mice. During the second week of Ang II infusion when blood pressures between groups diverged, DC AT1aR KO mice excreted less sodium than WTs. Expressions for epithelial sodium channel subunits were increased in DC AT1aR KO kidneys. CONCLUSIONS: Following activation of the renin angiotensin system, AT1aR stimulation on DCs suppresses renal DC maturation and T cell activation with consequent protection from sodium retention and blood pressure elevation.

A rat model of acute kidney injury caused by multiple subcutaneous injections of Asian giant hornet (Vespa mandarina Smith) venom.

A model of acute kidney injury (AKI) caused by multiple subcutaneous injections of Asian giant hornet (Vespa mandarina Smith) venom was developed in male Wistar rats. The rats were injected subcutaneously at multiple sites in the dorsal region with a total venom dose of 5 mg/kg. Blood samples were obtained 8, 24 and 48 h after venom injection for the quantification of various biochemical parameters and assessment of renal function. Wasp venom caused significant increases in all biochemical parameters (aspartate aminotransferase, creatine kinase, free hemoglobin, lactate dehydrogenase, myoglobin, and plasma creatinine) within 8 h of venom administration, as well as marked alterations in renal function (a decrease in glomerular filtration rate leading to oliguria). The biochemical parameters showed varying degrees of recovery but remained elevated to varying degrees after 48 h, whereas the glomerular filtration rate showed no recovery during this period. The histopathological alterations consisted primarily of acute tubular necrosis, with tubular epithelial cell sloughing and loss of tubule brush border. This profile of biochemical and functional alterations was similar to that seen in human envenomations by this species, suggesting that this animal model may be useful for understanding the pathophysiology of AKI caused by this wasp venom.

IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage.

Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.

A retrospective cohort study comparing high and low balloon inflation pressure on technical success and patency for treating central venous lesions in patients on chronic hemodialysis.

BACKGROUND: We aimed to analyze the success rates and the access patency rates at 12 months between patients on chronic hemodialysis with symptomatic central venous stenosis (CVS) or occlusion (CVO), receiving high or low balloon inflation pressure for treatment. METHODS: We performed a retrospective study in which angioplasty balloons were inflated using a low-pressure or a high-pressure for the management of hemodialysis patients with CVS/CVO. The outcomes of this study were the success rate and the access patency rates at 12 months after balloon angioplasty, and the differences between groups were compared. RESULTS: We included a total of 74 patients on hemodialysis and assigned them to the low-pressure or the high-pressure groups. Success rates in patients of the high-pressure group (94.12%) were higher than those in patients of the low-pressure group (67.50%) (p = 0.005). With a total of 59 patients with technical success, at 6 and 12 months after angioplasty, the rates of access patency in the low-pressure group were 68 and 48%, respectively; on the other hand, the primary patency rates in the high-pressure group were 86.67% (6-months) and 76.67% (12-months). The 6 and 12 months post-interventional patency rates were higher in patients of the high-pressure group than those in patients of the low-pressure group (p = 0.10 at 6 months and p = 0.03 at 12 months). CONCLUSIONS: Compared to balloon angioplasty using a low inflation pressure, hemodialysis patients with CVS/CVO receiving angioplasty using a high inflation pressure have significantly higher technical success and 12-month patency rates.

The Association between Changes in Low Parathyroid Hormone Levels and Cardiac Function Decline in Maintenance Hemodialysis Patients: A Prospective Observational Study.

OBJECTIVES: The aim of this study was to investigate a possible association between changes in low parathyroid hormone (PTH) levels and cardiac function decline in maintenance hemodialysis (MHD) patients. METHODS: A total of 150 MHD patients were included and followed for 24 months. The enrolled patients were divided into 3 groups based on their PTH status at baseline and 24 months. Factors potentially involved in changes in the PTH level and cardiac function were compared using multivariate logistic regression analysis. RESULTS: At 24 months, the presence of low PTH levels increased by 26.7%. The main independent factors for low PTH levels were a low BMI, hemoglobin, and serum albumin and high serum calcium (p < 0.05). A persistently low PTH level at 24 months was associated with a decrease in the left ventricular ejection fraction (LVEF) and increase in valvular calcification (p < 0.05). Additionally, a decrease in PTH levels from normal or high to low values was associated with a decrease in LVEF and cardiac output (CO) and an increase in valvular calcification (p < 0.05). Furthermore, compared with those of the persistently low PTH level group, LVEF values were lower at 24 months in the group with a decrease from high/normal to low PTH level (p < 0.05). CONCLUSION: Persistently low PTH levels and changes in the PTH level from high/normal to low were associated with cardiac function decline in MHD patients. Moreover, a PTH level change from high/normal to low showed a stronger correlation with cardiac function decline.

Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration.

The transcription factor Twist1 regulates several processes that could impact kidney disease progression, including epithelial cell differentiation and inflammatory cytokine induction. Podocytes are specialized epithelia that exhibit features of immune cells and could therefore mediate unique effects of Twist1 on glomerular disease. To study Twist1 functions in podocytes during proteinuric kidney disease, we employed a conditional mutant mouse in which Twist1 was selectively ablated in podocytes (Twist1-PKO). Deletion of Twist1 in podocytes augmented proteinuria, podocyte injury, and foot process effacement in glomerular injury models. Twist1 in podocytes constrained renal accumulation of monocytes/macrophages and glomerular expression of CCL2 and the macrophage cytokine TNF-α after injury. Deletion of TNF-α selectively from podocytes had no impact on the progression of proteinuric nephropathy. By contrast, the inhibition of CCL2 abrogated the exaggeration in proteinuria and podocyte injury accruing from podocyte Twist1 deletion. Collectively, Twist1 in podocytes mitigated urine albumin excretion and podocyte injury in proteinuric kidney diseases by limiting CCL2 induction that drove monocyte/macrophage infiltration into injured glomeruli. Myeloid cells, rather than podocytes, further promoted podocyte injury and glomerular disease by secreting TNF-α. These data highlight the capacity of Twist1 in the podocyte to mitigate glomerular injury by curtailing the local myeloid immune response.

Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor.

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II)-dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

Twist1 in T Lymphocytes Augments Kidney Fibrosis after Ureteral Obstruction.

Background: Twist1 is a basic helix-loop-helix domain-containing transcription factor that participates in diverse cellular functions, including epithelial-mesenchymal transition and the cellular immune response. Although Twist1 plays critical roles in the initiation and progression of kidney diseases, the effects of Twist1 in the T lymphocyte on the progression of renal fibrosis require elucidation. Methods: 129/SvEv mice with a floxed allele for the gene encoding Twist1 or TNFα were bred with CD4-Cre mice to yield CD4-Cre+ Twist1flox/flox (Twist1-TKO) or CD4-Cre+ TNFflox/flox (TNF-TKO) mice with robust, but selective, deletion of Twist1 or TNFα mRNA in T cells, respectively. Twist1 TKO, TNF TKO, and WT controls underwent UUO with assessment of kidney fibrosis and T-cell phenotype at 14 days. Results: Compared with WT controls, obstructed kidneys from Twist1 TKO mice had attenuated extracellular matrix deposition. Despite this diminished fibrosis, Twist1 TKO obstructed kidneys contained more CD8+ T cells than in WTs. These intrarenal CD8+ T cells exhibited greater activation and higher levels of TNFα expression than those from WT obstructed kidneys. Further, we found that selective deletion of TNFα from T cells exaggerated renal scar formation and injury after UUO, highlighting the capacity of T-cell TNF to constrain fibrosis in the kidney. Conclusions: Twist1 in T cells promotes kidney fibrogenesis, in part, by curtailing the renal accumulation of TNF-elaborating T cells.

Role of collectin-11 in innate defence against uropathogenic Escherichia coli infection.

Classical collectins (surfactant protein A and D) play a significant role in innate immunity and host defence in uropathogenic Escherichia coli (UPEC)-induced urinary tract infection (UTI). However, the functions of collectin-11 (CL-11) with respect to UPEC and UTI remain largely unexplored. This study aimed to investigate the effect of CL-11 on UPEC and its role in UTI. We further examined its modulatory effect on inflammatory reactions in proximal tubular epithelial cells (PTECs). The present study provides evidence for the effect of CL-11 on the growth, agglutination, binding, epithelial adhesion and invasion of UPEC. We found increased basal levels of phosphorylated p38 MAPK and human cytokine homologue (keratinocyte-derived chemokine) expression in CL-11 knockdown PTECs. Furthermore, signal regulatory protein α blockade reversed the increased basal levels of inflammation associated with CL-11 knockdown in PTECs. Additionally, CL-11 knockdown effectively inhibited UPEC-induced p38 MAPK phosphorylation and cytokine production in PTECs. These were further inhibited by CD91 blockade. We conclude that CL-11 functions as a mediator of innate immunity via direct antibacterial roles as well as dual modulatory roles in UPEC-induced inflammatory responses during UTI. Thus, the study findings suggest a possible function for CL-11 in defence against UTI.

COX-2-independent activation of renal (pro)renin receptor contributes to DOCA-salt hypertension in rats.

It has been shown that cyclooxygenase (COX)-2-dependent activation of renal (pro)renin receptor (PRR) contributes to angiotensin II (ANG II)-induced hypertension. However, less is known about the involvement of this mechanism in ANG II-independent hypertension. The goal of the present study was to test whether or not COX-2-dependent upregulation of PRR serves as a universal mechanism contributing to ANG II-dependent and -independent hypertension. Here, we examined the association between renal COX-2 and PRR during deoxycorticosterone acetate (DOCA)-salt hypertension in rats. By immunoblot analysis and immunofluorescence, renal protein expression of PRR was remarkably upregulated by DOCA-salt treatment. Surprisingly, this upregulation of renal PRR expression was unaffected by a COX-2 inhibitor, celecoxib. To address the role of renal PRR to the pathogenesis of DOCA-salt hypertension, a decoy PRR inhibitor, PRO20, was infused to the renal medulla of uninephrectomized Sprague-Dawley rats for 14 days. Radiotelemetry demonstrated effective attenuation of DOCA-salt hypertension by intramedullary infusion of a PRR inhibitor, PRO20. In parallel, DOCA-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied with blunted polydipsia and polyuria. In contrast, intravenous infusion of PRO20 was less effective in attenuating DOCA-salt hypertension and cardiorenal injury. Together, these results suggest that COX-2-independent activation of renal PRR contributes to DOCA-salt hypertension.