bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0519HEXARELIN PROTECTS ISCHEMIA REPERFUSION INDUCED ACUTE KIDNEY INJURY BY TARGETING 14-3-3Σ
Authors: Guan Chen , Xu Yan 
Published: June 2020

Abstract

Background and Aims
Acute kidney injury (AKI), manifested as a sudden decline in renal function on the order of days or a week, is one of the most common complications and is strongly associated with renal prognosis, medical expenses and length of stay of hospitalized patients. However, incidence of AKI can be reduced by early intervention. Hexarelin is a synthetic analogue of ghrelin with a potent GH releasing activity, which is also found to exhibited a significant protectant activity against postischemic ventricular dysfunction in isolated perfused hearts subjected to low flow ischemia and reperfusion. This study aims to explore the effects of hexarelin on ischemia reperfusion induced acute kidney injury (I/R-AKI) and the underlying mechanism of it.

Method
Thirty healthy male SPF SD aged at 8 weeks weighing 250-300g rats were divided into 5 groups including normal group, sham operation group, acute kidney injury (AKI) group, acute kidney injury group after hexarelin (HEX + AKI), and acute kidney injury group after saline (Saline + AKI). Bilateral kidney artery clamping was applied for 50 min to induce AKI. The drug-administered group and the saline-controlled group rats were treated with intraperitoneal injections 7 days before modelling and the Hex + AKI group and the saline + AKI group were given Hexarelin (dose 100 μg/kg. d) and equal volume of saline, respectively. To explore the underlying mechanism of HEX on I/R-AKI, gene expression profiling of AKI samples were searched from Pubmed, GEO dataset. Differential expression genes were used to predict canonical signal transduction pathways and signalling networks. Molecular docking was used to predict the combination of hub proteins and HEX.

Results
1) Renal function in HEX-pretreated rats was significantly improved compared with control group: HE results showed that renal tubules were less dilated and rebuilt after pretreatment, and the infiltration area was significantly reduced; serum creatinine (P = 0.0005 &lt;0.05), urea nitrogen (P &lt;0.0001) concentration were significantly reduced; RT-qPCR showed that relative expression of Kim-1 (P&lt;0.0001), caspase3 (P = 0.007), Bax (P &lt;0.0001), Bad (P = 0.0168 &lt;0.05) in HEX+AKI group were significantly decreased while the relative expression of Bcl-2 (P &lt;0.05) was significantly increased compared with saline treated rats;
2) Microarray data analysis showed that 63 differential expression genes including SFN, Cyr61, Kim-1 were hub genes in the development of I/R-AKI;
3) Three-dimensional structure of the hub proteins HEX were obtained from the SWISS-MODEL database and the PubChem compound database, and Autodock software was used to calculate the molecular docking between proteins and HEX. Results showed that HEX and the protein that encoded by the gene SFN (SFN, 14-3-3σ) binding stably with a binding energy of -8.51;

Conclusion
Hexarelin protects ischemia reperfusion induced acute kidney injury by targeting 14-3-3σ.
P0521TICAGRELOR PROTECTS KIDNEY FROM SEPSIS INDUCED ACUTE KIDNEY INJURY THROUGH ADENOSINE DEPENDENT WAY
Authors: Cao Yuhan , Xu Qiancheng , Wang Yuwei , Fu Cong 
Published: June 2020

Abstract

Background and Aims
Sepsis induced acute kidney injury (AKI) is common in intensive care unit in multiple organ failure patients. Ticagrelor is an anti-platelet drug that widely applied in coronary artery disease. In addition, ticagrelor can increase the level of adenosine. Recent study had indicated that ticagrelor can protect renal function in sepsis induced AKI. However, the detailed mechanism was still unknown. Accordingly, we designed this trial to investigate if the ticagrelor alleviated sepsis induced AKI and demonstrated the potential mechanism that how ticagrelor works.

Method
C57BL6J mouse received oral ticagrelor (20mg/kg and 50mg/kg) for 7 days and caecum ligation and puncture (CLP) were performed. Adenosine-receptor antagonist was administered (10mg/kg, intraperitoneal injection) to block the adenosine pathway 2h before CLP. After 24h, serum creatinine was measured. PAS staining was used and TUNEL staining was applied to determine the pathological changes and cell apoptosis. Plasma concentrations of TNF-α and IL-1β were detected. Kidney tissue level of TNF-α and IL-1β were determined via qRT-PCR. Western blot was used to determine the expression of signal molecular in kidney.

Results
In ticagrelor group, PAS staining (fig. 1) showed that less swelling of renal tubules and TUNEL staining (fig. 2) showed the less cell apoptosis compared to CLP. Serum creatinine was significantly lower in ticagrelor group. Plasma TNF-α and IL-1β and kidney expression of TNF-α and IL-1β were significantly lower in ticagrelor group. Adenosine-receptor antagonist significantly blocked the effect of ticagrelor (fig. 3 ang 4). Western blot showed that ticagrelor activate the phosphorylation of AKT and mTOR in kidney. Adenosine-receptor antagonist inhibited the activation of AKT and mTOR (fig. 5).

Conclusion
The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of phosphorylation of AKT and mTOR in sepsis induced AKI.
P0523PROTECTIVE ROLE OF REGULATORY B CELLS ON THE RENAL TISSUE REPAIRMEN AFTER ISCHEMIA REPERCUSSION INJURY
Authors: Yunosuke Yokota , Kodama Goh , Itou Sakuya , Nakayama Yosuke , Komatsu Nobukazu , Mizoguchi Atsushi , Fukami Kei 
Published: June 2020

Abstract

Background and Aims
Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end- stage renal disease. It has been postulated that interleukin-10 (IL-10)-producing Regulatory B cells (Breg) play an important role for the tissue repairment in several tissues and organs. Basically, protective role of Breg has been reported in inflammatory bowel disease. In the kidney, it has been shown that IL-10 suppresses renal function decline and improves renal prognosis in IRI model, a typical model of AKI. However, the identity of Breg in the kidney and their origin have not been clarified. Further, how the Breg works during the transition from AKI to CKD is not known. Therefore, first we investigated whether Breg existed in renal tissue on the progression from AKI to CKD in IRI model mice. Further, we performed splenectomy, and examined the renal injury, Breg, and plasma IL-10 levels in this model.

Method
To examine the existence of Breg in the kidney of IRI model, we used 8-10 weeks-old GFP / IL-10 mice based on C57BL / 6J mice. They are reporter mice for IL-10 producing cells, and can visualize IL-10 producing cells under a fluorescence microscope without fluorescent immunostaining. We prepared following three groups, sham, IRI (unilateral), and IRI + SN (splenectomy) groups. Mice were anesthetized with chloral hydrate (4 g/kg,, intraperitoneal). After making a midline incision, exposed a blood vessel of the left renal pedicles and clamped it for 30 min by clips. one day, 7 days, and 14 days after the surgery, mice were sacrificed, and renal function and plasma IL-10 levels as well as tissue damages by PAS and Masson’s Trichrome staining were assessed. Tissue IL-10-producing cells were detected by flow cytometry.

Results
There was no difference of plasma IL-10 levels and renal tubulointerstitial injury in IRI group and IRI+SN group on day 1 after IRI. However, on day 7 and day 14, plasma IL-10 levels became gradually higher in IRI group, and SN decreased the increase in IL-10 levels. Tubulointerstitial injury was induced by IRI and SN further worsened tubular damages. Serum Cr and BUN levels were not different in three groups due to normal right kidney. On day 1, number of IL-10-producing B cells increased in the spleen and renal medulla in IRI group confirmed by flow cytometry, which was completely diminished by SN, suggesting that origin of the infiltrated Breg might be spleen, thereby being involved in the protective role in IRI injury in the kidney.

Conclusion
We report for the first time that Breg might be recruited from spleen by AKI, which may be one of the mechanisms to prevent the progression to CKD.
P0530A NOVEL LNCRNA(LRAN9884) PROMOTES AKI VIA MAINTAINING MINCLE-DEPENDENT M1 MACROPHAGE PHENOTYPE
Authors: Zhang Yingying , Yu Chen 
Published: June 2020

Abstract

Background and Aims
Macrophages are key inflammatory cells and play a critical role in renal inflammation in acute kidney injury (AKI). M1 inflammatory macrophage and M2 anti-inflammatory macrophage act reverse role. Phenotype of macrophages is highly flexible and can be changed over time. However, the underlying mechanism of M1 and M2 macrophage phenotype switching during AKI is still largely unclear. In our previous study, we identified a novel lncRNA (LRNA9884) might contribute to inflammation according to modifying macrophages. The present study was designed to uncover the pathogenic role and the underlying mechanism of LRNA9884 in cisplatin-induced AKI.

Method
Expression level and pattern of LRNA9884 were examined in cisplatin-induced AKI mice. The regulatory mechanisms of LRNA9884 was investigated in cultured bone marrow–derived macrophages (BMDMs) in vitro by silencing or overexpressing of LRNA9884. Flow Cytometer, fluorescence in situ hybridization (FISH) and other multiple molecular biological techniques were applied to figure out the role of LRNA9884 under acute kidney injury.

Results
LRNA9884 was significantly upregulated in the kidney of cisplatin-induced mice and was associated with the progression of the renal inflammation by using RT-PCR and ISH assay. FISH assay with immunoﬂuorescence co-staining detected that LRNA9884 was largely expressed in the nucleus of macrophage in cisplatin-induced mice kidney compared with the sham group at day 1 after AKI injury. LRNA9884 was remarkedly induced by TNF-α (10ng/ml) in BMDMs as time- and dose- dependent. Western blot and RT-PCR showed that silencing of LRNA9884 effectively inhibited upregulated of macrophage-inducible C-type lectin (Mincle) and iNOS induced by TNF-α. More importantly, we identified that LRNA9884 maintained M1 macrophages phenotype by triggering mincle production at transcriptional level as evidenced by ChIP assay.

Conclusion
LRNA9884 is a mincle-dependent lncRNA that highly-expressed in macrophages under AKI development. Targeting of LRNA9884 effectively blocked the inflammatory response via promoting the transition M1 macrophage to M2 macrophage phenotype. This study will shed new lights on the understanding of pathological role of novel LRNA9884 in AKI.
P0546EARLY, BUT NOT LATE, CONTRALATERAL NEPHRECTOMY OVERCOMES PROGRESSION TO CKD AFTER UNILATERAL ISCHEMIC INJURY
Authors: Moonen Lies , Cuesta-Apausa Cristina , Lopez-Hernandez Francisco J , Martinez Salgado Carlos , D'Haese Patrick , Vervaet Benjamin 
Published: June 2020

Abstract

Background and Aims
It is increasingly clear that acute kidney injury (AKI) can result in the development of chronic kidney disease (CKD) in humans. Murine renal unilateral ischemia-reperfusion injury (UIRI) models this AKI-to-CKD progression in the injured kidney in the presence of its healthy counterpart (Le Clef et al, Plos One 2016). In mice, we and others demonstrated that contralateral nephrectomy (Nx), when performed shortly after UIRI (i.e. 3 days), is able to significantly attenuate the progression to CKD. Although non-translatable, Nx can be considered an experimental therapeutic intervention that incites inherent physiological recovery mechanisms in the kidney. Here, we investigate in rats to what extent contralateral Nx is able to attenuate or revert CKD progression when performed well beyond the acute injury phase, i.e. with increased Nx delay time after UIRI.

Method
AKI was induced in male Wister rats by left UIRI for 60 min at 35°C core body temperature after which contralateral Nx was performed 3, 10 or 20 days later, or no Nx was performed. Control animals underwent sham-UIRI and sham-Nx 3 days later. Renal function was assessed by serum creatinine and transcutaneous GFR measurement 24h and 72h after Nx and weekly thereafter. Rats were euthanized 11 weeks after Nx. Kidneys were weighed and histology was evaluated by PAS stain for overall morphology and Sirius Red stain for interstitial fibrosis.

Results
When no Nx was performed, renal function of the injured kidney decreased 44% compared to control animals at week 11. Nx at day 3 induced full functional recovery from week 5 after Nx on, whereas Nx at day 10 and 20 both lead to a persistent 20% loss of renal function at week 9 after Nx (p&lt;0.05). Nx at day 3 was able to attenuate renal atrophy and fibrotic tubulointerstitial expansion. Nx at day 10 and 20 were less efficient and led to 1.6 (p&gt;0.05) and 2.6 (p&lt;0.05) fold increase of tubulointerstitial area compared to controls. Nx at day 3 and 10 induced a significant increase in renal mass-to-body weight ratio compared to control from 2.9±0.1 mg/g (control) to 4.6±0.4 mg/g (day 3) and 4.8±0.3 mg/g (day 10) respectively. When Nx was performed at day 20 or no Nx was performed, renal mass-to-body weight ratio did not differ significantly from control animals, however, parallel with renal function, histopathology was considerably worse.

Conclusion
Early contralateral Nx after UIRI rescues renal function and morphology, whereas delayed Nx does not allow full recovery of the injured kidney. There was no additional functional loss when Nx was performed on day 20 versus day 10, though, histopathology aggravated. These results imply that a damaged kidney loses its intrinsic (compensatory) recovery potential over time and that an early intervention is crucial for averting CKD outcome after AKI.
P0547THE DELETION OF AKT1 ATTENUATES RENAL FIBROSIS AND TUBULAR EPITHELIAL-MESENCHYMAL TRANSITION DURING ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE PROGRESSION
Authors: Ye Byung Min , Kim Il Young , Kim Min Jeong , Lee Soo Bong , Lee Dong Won , Song Sang Heon , Seong Eun Young 
Published: June 2020

Abstract

Background and Aims
Acute kidney injury (AKI) is an underestimated, yet important risk factor for the development of chronic kidney disease (CKD), which is characterized by the tubulointerstitial fibrosis and tubular epithelial-mesenchymal transition (EMT). Akt has been reported to be involved in renal fibrosis and EMT. Thus, we investigated the role of Akt1, one of the three Akt isoforms, in the murine model of AKI to CKD progression.

Method
We subjected the wild type and Akt1−/− mice to unilateral ischemia-reperfusion injury (UIRI). UIRI was induced by clamping the left renal artery for 30 min followed by reperfusion. After 6 weeks of UIRI, the renal fibrosis and EMT were assessed by histology, immunohistochemistry, and western blot.

Results
After 6 weeks after UIRI, we found that Akt1, not Akt2 or Akt3, was activated in UIRI-kidney. The tubulointerstitial fibrosis was significantly alleviated in Akt1−/− mice compared with the wild type (WT) mice. Besides, the deletion of Akt1 decreased the expression of the vimentin and α-SMA and increased the expression of E-cadherin, indicating the suppression of tubular EMT. However, there was no difference in the activity of TGF-β1/Smad signalling, which is the potent inducer of renal fibrosis and EMT, between WT mice and Akt1−/− mice. The deletion of Akt1 also increased the GSK-3β activity and decreased the expression of β-catenin, Snail, and twist1.

Conclusion
Our findings demonstrate that the deletion of Akt1 attenuates the renal fibrosis and tubular EMT independently of TGF-β1/Smad signalling during the AKI to CKD progression. Akt1 may be the therapeutic target against the AKI to CKD progression.
P0548PAC-MEDIATED AKI PROTECTION IS CRITICALLY MEDIATED BUT DOES NOT EXCLUSIVELY DEPEND ON CELL-DERIVED MICROVESICLES
Authors: Patschan Daniel , Schwarze Katrin , Ritter Oliver , Patschan Susann , Müller Gerhard Anton 
Published: June 2020

Abstract

Background and Aims
Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (EV). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived EV and / or the secretome alone.

Method
AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI - 40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. The four mediators were chosen since previous own studies showed improved PAC-mediated AKI protection after cell preconditioning with these substances. PAC-derived EV and the vesicle-depleted supernatant were subsequently collected and i.v. injected post-ischemia. Mice were analyzed 48 hours later.

Results
IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of EV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: EV+Ang-1, EV+BMP-5, EV+melatonin, and EV+secretome+Ang-1.

Conclusion
Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived EV. The secretome, either collected from native or preconditioned cells does not prevent mice from ischemia-induced dysfunction. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection. We suggest, that the mere presence of intact cells in the post-ischemic tissue is necessary for improving functional and structural outcome parameters under certain conditions.
P0549ESSENTIAL ROLES OF TESTOSTERONE IN MALE KIDNEY MATURATION AND REPAIR AFTER INJURY
Authors: Sato Yuki , Uchino Eiichiro , Kitai Yuichiro , Oguchi Akiko , Yanagita Motoko 
Published: June 2020

Abstract

Background and Aims
The newborn kidneys are structurally and functionally immature. They mature after birth to adapt to extra-uterine life, yet the comprehensive changes of the kidney have not been defined. We investigated the structural and functional changes in the kidney after weaning and examined the effect of testosterone in this maturation process in male mice.

Method
We performed phenotypic analysis of male mouse kidneys as well as those subjected to castration utilizing a combination of histological analysis, bulk transcriptome analysis, charged metabolite analysis by CE-TOFMS and brush border membrane vesicles LC-MS/MS analysis.

Results
Bulk transcriptome analysis of postnatal 3 and 8 week male kidneys showed the gene sets enriched in 8w included those associated with metabolic process and transporters in proximal tubule, and structural analysis revealed proximal tubule elongation and hypertrophy in 8 weeks. Most differentially expressed genes (DEGs) identified above were induced between postnatal day 28 and 40, a period of testosterone surge, and were closely correlated with DEGs between adult male and female kidneys. These structural and gene expression changes during maturation were mostly cancelled by castration before testosterone surge. Proximal tubules expressed androgen receptor, and some of these DEGs were upregulated or downregulated by the administration of testosterone in cultured proximal tubules. Consistent results with DEGs were also confirmed at protein levels and related metabolites in vivo. For instance, induction of cystine transporter SLC7A13 expression as well as the increase in cysteine and cysteine-glutathione disulphide-Divalent in the kidney were confirmed during this period. Fatty acid β-oxidation enzymes were also increased during this period. Some of the down-regulated genes across puberty were reactivated after injury and returned to the basal levels with repair.

Conclusion
Proximal tubules are the main site of maturation after weaning, and acquire the abilities to absorb and metabolize a variety of filtered substances and to increase energy metabolism, which were mainly driven by testosterone.
P0569ACUTE KIDNEY INJURY AFTER LUNG TRANSPLANTATION: INCIDENCE, RISK FACTORS AND OUTCOMES IN A MONOCENTRIC RETROSPECTIVE COHORT STUDY
Authors: Gandolfo Maria Teresa , Bellincioni Cecilia , Morlacchi Letizia Corinna , Rossetti Valeria , Blasi Francesco B , Messa Piergiorgio 
Published: June 2020

Abstract

Background and Aims
Acute kidney Injury (AKI) occurs in more than 50% of patients after lung transplantation (LTx). Our aim was to describe the incidence, risk factors and outcomes associated with AKI after LTx in a retrospective monocentric cohort study.

Method
We studied all recipients of LTx (&gt; 16 years of age) occurring at Ospedale Maggiore Policlinico Milano between Jan 1st 2015 and Dec 31st 2017. AKI was defined according to KDIGO classification, eGFR was calculated according to CKD (Chronic Kidney Disease) Epidemiology Collaboration formula and CKD was defined by an eGFR&lt; 60 ml/min per 1.73 m2. Chi square, Fisher exact test, t.-test and logistic regression were used to define risk factors for AKI in the early post-surgical period and for CKD at 1 and 2 years after LTx. AKI-related survival was estimated using Kaplan Meyer model.

Results
Of 78 LTx patients enrolled in our Center, 50% of patients was affected by cystic fibrosis. Median age at transplant was 43 years (27-55); median follow- up was 31 months (20-40). Survival rate was 80.77% at 1 year, 69.23% at 2 years and 66.67% on Dec 31st 2019 (last follow-up).
AKI occurred in 42 (53.85%) patients within the first week after LTx, respectively grade I and II in 12 each (15.38%) and grade III in 18 (23.08%) patients.
Pre-transplant low albumin levels and hypertension were independently associated with AKI at univariate and multivariate (p= 0.0018 and 0.0004 respectively) analysis. Pre-transplant low albumin levels, pre-transplant ECMO-use, hypertension, ECMO-use during transplant surgery were associated with severe AKI in univariate analysis but only pre-transplant hypertension and ECMO-use during transplant surgery were independently associated in the multivariate one (p=0.0266 and 0.0463 respectively).
Survival was significantly reduced in patients affected by AKI (p=0.035); this observation became strongly significant when only mild and moderate (grade I and II) AKI was considered (p=0.0071).
CKD was diagnosed in 38.09% of patients at 1 year and 35.18% at 2 years.
While numerous risk factors were related to the occurrence of CKD at 1 and 2 years after LTx at univariate analysis, only grade III AKI remained independently associated with CKD at multivariate analysis (p= 0.0081 for 1 year-CKD, p=0.0154 for 2 year-CKD).

Conclusions
In our population, AKI after LTx occurred in about half of the patients and was predicted by history of hypertension, low albumin levels and hemodynamic instability during the surgery. Mild-moderate AKI, often clinically underestimated, was strongly associated with reduced survival. Severe forms of AKI were predictive of occurrence of CKD.