scholarly journals Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

2020 ◽  
Vol 21 (20) ◽  
pp. 7527 ◽  
Author(s):  
Christina Mertens ◽  
Laura Kuchler ◽  
Anna Sola ◽  
Roser Guiteras ◽  
Stephan Grein ◽  
...  
Keyword(s):  
Renal Injury ◽  
Cultured Cells ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Iron Loading ◽  
Lipocalin 2 ◽  
Patient Death ◽  
Short Term ◽  
Cellular Source

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.

scholarly journals P0524PERICYTE IS ESSENTIAL FOR RENAL TUBULAR CELL REGENERATION AFTER ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yu-Hsiang Chou ◽  
YU-HAN SHAO ◽  
SHUEI-LIONG LIN
Keyword(s):  
Acute Kidney Injury ◽  
Growth Factor ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Renal Tubular Cell ◽  
Inflammatory Factor ◽  
Control Groups ◽  
Renal Regeneration

Abstract Background and Aims Pericyte-myofibroblast transition is activated after acute kidney injury (AKI) and is the major mechanism of ensuing chronic kidney disease (CKD). Nevertheless, the role of pericyte in renal regeneration after AKI has not been deeply investigated. Many studies have shown that pericyte can secret growth factors such as fibroblast growth factor 1 and 7 (FGF-1, FGF-7) and is essential for structure support and vascular integrity in normal kidney. We supposed that the ablation or inhibition of pericytes during AKI would retard renal repair. Method Our study demonstrated that activated pericytes/myofibroblast was beneficial for renal regeneration after AKI. We here performed pericyte ablation and pericyte inhibition after ischemia-reperfusion renal injury by using transgenic mice such as Gli1-CreERT2;iDTR mice and blockade of platelet-derived growth factor receptor β (PDGFRβ), respectively. Results Renal injury was more severe and renal recovery was worse in groups of pericyte ablation or inhibition compared to control groups. Ki67 positive tubular cells which indicated renal regeneration were much more in control groups than that in groups of pericyte ablation or inhibition. We also found higher macrophage number as well as higher inflammatory factor including tumor necrosis factor-α and interleukin-1β which indicated more severe inflammation in groups of pericyte ablation or inhibition. Conclusion These studies suggest that pericytes play a beneficial role during renal recovery after AKI. These findings delineate the adequate timing when we target on pericyte/myofibroblast to ameliorate renal fibrosis and avoid to impede renal regeneration at the same time. Further research is still needed to clarify the change of specific gene and signalling pathway after pericyte ablation or inhibition. These are promising findings that provide opportunities to develop new targets to promote AKI recovery and to ameliorate renal fibrosis.

scholarly journals Melatonin Alleviates Renal Injury in Mouse Model of Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Liyang Chen ◽  
Zhijian Han ◽  
Zhiguang Shi ◽  
Chao Liu ◽  
Qiulun Lu
Keyword(s):  
Renal Injury ◽  
Oxidant Stress ◽  
Mrna Level ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Role ◽  
Cecal Ligation Puncture ◽  
Species Production

Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.

scholarly journals Urinary Mitochondrial DNA Identifies Renal Dysfunction and Mitochondrial Damage in Sepsis-Induced Acute Kidney Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Qiongyuan Hu ◽  
Jianan Ren ◽  
Huajian Ren ◽  
Jie Wu ◽  
Xiuwen Wu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Renal Dysfunction ◽  
Renal Injury ◽  
Cecal Ligation ◽  
Surrogate Marker ◽  
Kidney Injury ◽  
Plasma Creatinine ◽  
Acute Renal Dysfunction

Background. Recent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI). Methods. We isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function. Results. A total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney. Conclusion. An elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

scholarly journals Impact of diabetes mellitus on short-term prognosis, length of stay, and costs in patients with acute kidney injury: A nationwide survey in China

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250934
Author(s):  
Lishan Tan ◽  
Li Chen ◽  
Yan Jia ◽  
Lingyan Li ◽  
Jinwei Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Acute Kidney Injury ◽  
Length Of Stay ◽  
Hospital Mortality ◽  
Kidney Injury ◽  
Nationwide Survey ◽  
Renal Recovery ◽  
Short Term ◽  
Increased Risk ◽  
Male Preponderance

Background International data suggest that people with diabetes mellitus (DM) are at increased risk for worse acute kidney injury (AKI) outcomes; however, the data in China are limited. Therefore, this study aimed to describe the association of DM with short-term prognosis, length of stay, and expenditure in patients with AKI. Methods This study was based on the 2013 nationwide survey in China. According to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) and expanded criteria of AKI, 7604 patients with AKI were identified, and 1404 and 6200 patients were with and without DM, respectively. Clinical characteristics, outcomes, length of stay, and costs of these patients were compared. Multivariate regression analyses were conducted to evaluate the association of DM with mortality, failed renal recovery, length of stay, and costs. Results Patients with AKI and DM were older, had higher male preponderance (61.9%), presented with more comorbidities, and had higher serum creatinine levels compared with those without DM. An apparent increase in all-cause in-hospital mortality, length of stay, and costs was found in patients with DM. DM was not independently associated with failed renal recovery (adjusted OR (95%CI): 1.08 (0.94–1.25)) and in-hospital mortality (adjusted OR (95%): 1.16 (0.95–1.41)) in multivariate models. However, the diabetic status was positively associated with the length of stay (β = 0.06, p<0.05) and hospital expenditure (β = 0.10, p<0.01) in hospital after adjusting for possible confounders. Conclusion In hospitalized AKI patients, DM (vs. no DM) is independently associated with longer length of stay and greater costs, but is not associated with an increased risk for failed renal recovery and in-hospital mortality.

Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases

2015 ◽  
Vol 93 (6) ◽  
pp. 443-450 ◽  
Author(s):  
Hala Salah Abdel kawy
Keyword(s):  
Renal Injury ◽  
Cecal Ligation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Serum Levels ◽  
Renal Perfusion ◽  
Protein Carbonyls ◽  
Necrosis Factor Alpha ◽  
Inflammatory Parameters ◽  
The Impact

Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor-alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis.

MO382POTASSIUM DISTURBANCES AND CHARACTERISTICS OF RENAL RECOVERY IN 1519 CONSECUTIVE PATIENTS WITH ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Christina Montgomerie ◽  
Jonas Spaak ◽  
Marie Evans ◽  
Stefan H Jacobson
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Resource Planning ◽  
Renal Recovery ◽  
Partial Recovery ◽  
Short Term ◽  
Early Recovery ◽  
Increased Risk ◽  
Severe Hyperkalemia

Abstract Background and Aims Acute kidney injury (AKI) is a common condition occurring in about 15% of hospitalized patients, often complicated by hyperkalemia causing increased risk for adverse cardiovascular events. The level of AKI (prerenal, renal or postrenal), is of importance as both pathophysiology and prognosis differ. Although early recovery from AKI is associated with less morbidity and mortality, patients with a history of AKI have a higher long-term risk of end-stage kidney disease and death. Most AKI studies include critically ill patients treated at intensive care units; less is known about AKI patients in general. The aim of this large single-center study was to report potassium disturbances and short-term hospital outcomes in 1519 consecutive patients with AKI admitted to a nephrology department. Methods All patients diagnosed with AKI between 2009 and 2018 and admitted to the nephrology department at Danderyd University Hospital, Stockholm, Sweden, were screened. Patients who fulfilled the KDIGO 2012 definition of AKI, a sCreatinine (sCr) &gt;1.5 times baseline or increase by &gt;0.3 mg/dL (&gt;26.5 mmol/L), were included. Potassium levels at admission were classified into hypokalemia (&lt;3.5 mmol/L), normokalemia (3.5-4.9 mmol/L), mild hyperkalemia (5-5.4 mmol/L), moderate (5.5-5.9 mmol/L) and severe hyperkalemia (≥6 mmol/L). Partial recovery was defined as an in-hospital sCr decrease by at least 30% while modest recovery was defined as s sCr decrease by at least 50%. Using logistic regression with conditional backward selection, we determined which variables that were associated with a partial recovery or a hyperkalemia (&gt;5 mmol/L). Patients on dialysis treatment were excluded. Patients were followed until either discharge or death, whichever came first. Results In 1519 patients with AKI, the majority (n=687 (45%)) had prerenal AKI, followed by AKI on chronic (defined as chronic kidney disease combined with any type of AKI) (n=536 (35%)), renal (n=166 (11%)) and postrenal AKI (n=130 (9%)). At admission, 30% of patients had any hyperkalemia, whereas 7% had severe hyperkalemia. Normokalemia was seen in 60% of the patients while 10.5% had hypokalemia. The more hyperkalemia, the higher level of sCr at admission, the more acidosis and the less proteinuria. Proteinuria was most pronounced in patients with mild hyperkalemia and normokalemia. In-hospital partial renal recovery was seen in 63% of the patients, while 38% had a modest recovery. Mortality during hospitalization was 4%; most of these patients had normokalemia (58%), followed by mild (18%) and moderate hyperkalemia (15%). In the prerenal and postrenal groups, most patients had a partial renal recovery (76% and 73% respectively). In patients with renal and AKI on chronic the proportions were lower (40% and 51%, respectively). Conclusion This study provides data from a large, contemporary AKI patient cohort under nephrology care. Severe potassium disturbances are common and short-term outcomes differ substantially in patients of variable AKI level and etiology. These findings have important implications for prognostic evaluation upon admission and further resource planning.

scholarly journals Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3133
Author(s):  
Wiwat Chancharoenthana ◽  
Kanyarat Udompronpitak ◽  
Yolradee Manochantr ◽  
Piyawat Kantagowit ◽  
Ponthakorn Kaewkanha ◽  
...  
Keyword(s):  
Renal Injury ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Erythropoietin Receptor ◽  
High Dose ◽  
Disease Characteristics ◽  
High Prevalence ◽  
Injury Models ◽  
Inflammatory Effect

Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients. Then, EPO was subcutaneously administered in mice with (i) cecal ligation and puncture (CLP) after renal injury including 5/6 nephrectomy (5/6Nx-CLP) and bilateral nephrectomy (BiNx-CLP) or sham surgery (sham-CLP) and (ii) lipopolysaccharide (LPS) injection, along with testing in macrophages. In patients, the data of EPO administration and the disease characteristics in patients with sepsis-induced acute kidney injury (sepsis-AKI) were evaluated. As such, increased endogenous EPO was demonstrated in all sepsis models, including BiNx-CLP despite the reduced liver erythropoietin receptor (EPOR), using Western blot analysis and gene expression, in liver (partly through hepatocyte apoptosis). A high-dose EPO, but not a low-dose, attenuated sepsis in mouse models as determined by mortality and serum inflammatory cytokines. Furthermore, EPO attenuated inflammatory responses in LPS-activated macrophages as determined by supernatant cytokines and the expression of several inflammatory genes (iNOS, IL-1β, STAT3 and NFκB). In parallel, patients with sepsis-AKI who were treated with the high-dose EPO showed favorable outcomes, particularly the 29-day mortality rate. In conclusion, high-dose EPO attenuated sepsis with preconditioning renal injury in mice possibly through the macrophage anti-inflammatory effect, which might be beneficial in some patients.

IN VITRO METHODS FOR THE STUDY OF THE ADENOHYPOPHYSIAL FUNCTIONS TO SECRETE GONADOTROPHIN

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S27-S40 ◽  
Author(s):  
T. Kobayashi ◽  
T. Kigawa ◽  
M. Mizuno ◽  
T. Watanabe
Keyword(s):  
Cell Culture ◽  
Organ Culture ◽  
Cultured Cells ◽  
Cell Sheet ◽  
Short Term ◽  
Hypothalamic Extract ◽  
Numerous Cell ◽  
Single Cell Culture ◽  
Almost All

ABSTRACT There are several in vitro methods to analyse the function of the adenohypophysis or the mechanisms of its regulation. The present paper deals with single cell culture, organ culture and short term incubation techniques by which the morphology and gonadotrophin-secreting function of the adenohypophysis were studied. In trypsin-dispersed cell culture, the adenohypophysial cells showed extensive propagation to form numerous cell colonies and finally develop into a confluent monolayer cell sheet covering completely the surface of culture vessels. Almost all of the cultured cells, however, became chromophobic, at least at the end of the first week of cultivation, when gonadotrophin was detectable neither in the culture medium nor in the cells themselves. After the addition of the hypothalamic extract, gonadotrophin became detectable again, and basophilic or PAS-positive granules also reappeared within the cells, suggesting that the gonadotrophs were stimulated by the extract to produce gonadotrophin. In organ culture and short term incubation, the incorporation of [3H] leucine into the adenohypophysial cells in relation to the addition of hypothalamic extract was examined. It was obvious that the ability to incorporate [3H] leucine into the gonadotrophs in vitro was highly dependent upon the presence of the hypothalamic extract.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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