Schematic diagram of fisetin in LPS-induced septic AKI.
Fisetin modulated the activities of TLR4/Src-mediated NF-κB p65 and MAPK pathways, thus alleviating kidney inflammation and apoptosis in ...LPS-induced septic AKI.
Display omitted
•Fisetin is a polyphenolic flavonoid in many fruits and vegetables.•Fisetin alleviated kidney injury against LPS-induced septic AKI.•Fisetin inhibited LPS-induced kidney inflammation and apoptosis.•Fisetin inhibited renal Src-mediated NF-κB and MAPK signalling pathways in LPS-induced septic AKI.
Sepsis is defined as end-organ dysfunction resulting from the host’s inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown.
The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice.
The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression.
Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression.
Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways
Aims
Type 2 diabetes mellitus (T
2
DM) has a rising prevalence and gut microbiota involvement is increasingly recognized. Diabetic nephropathy (DN) is a major complication of T
2
DM. The aim of the ...study was to understand the gut–kidney axis by an analysis of gut microbiota composition among biopsy-proven DN, T
2
DM without kidney disease, and healthy control.
Methods
Fecal samples were collected from 14 DNs, 14 age/gender-matched T
2
DMs without renal diseases (DM), 14 age and gender-matched healthy controls (HC) and household contacts (HH) of DM group. The microbiota composition was analyzed by 16sRNA microbial profiling approach.
Results
Substantial differences were found in the richness of gut microbiota and the variation of bacteria population in DM compared to HC, and DN compared to DM, respectively. DM could be accurately distinguished from age/gender-matched healthy controls by the variable of genus
g_Prevotella_9
(AUC = 0.9), and DN patients could be accurately distinguished from age/gender-matched DM by the variables of two genera (
g_Escherichia-Shigella
and
g_Prevotella_9
, AUC = 0.86). The microbiota composition of HH group was close to that of HC group, and was different from DM group. Under the same diet, DM could be more accurately detected by the same genus (
g_Prevotella_9
, AUC = 0.92).
Conclusion
Gut microbiota composition was explored to be related to the occurrence of biopsy-proven DN from DM. DM could be distinguished from HC by detecting
g_Prevotella_9
level in feces, while DN was different from DM by the variables of
g_Escherichia-Shigella
and
g_Prevotella_9
, which potentially contributed to the physiopathological diagnosis of DN from DM.
ABSTRACT
Background
Chronic kidney disease (CKD) is a worldwide public health problem. Although accumulated data suggested that probiotic supplements played roles in CKD, the results remained ...controversial. Here, we performed a meta‐analysis to assess the effects of probiotic supplements on the CKD progression.
Methods
A systematic search was conducted through the PubMed, Embase and Cochrane databases until September 2018. Randomized controlled trials with control receiving placebo, evaluating the effects of probiotic supplements on CKD were included.
Results
A total of 10 randomized controlled trials in 8 countries were selected. In the meta‐analysis, urea level was significantly reduced in probiotics‐administrated non‐dialysis patients (mean differences (MD) = −30.01; 95% confidence interval (CI) = −56.78, −3.25; P = 0.03) while no significant change was found in the dialysis patients receiving probiotics (MD = 0.1; 95% CI = −9.28, 9.48; P = 0.98). Probiotic supplements also exhibited no effect on uric acid (MD = −0.43; 95% CI = −1.19, 0.33; P = 0.27), C‐reactive protein (MD = −0.48; 95% CI = −1.29, 0.33; P = 0.24), creatinine (MD = −0.18; 95% CI = −0.82, 0.47; P = 0.59), and estimated glomerular filtration rate (MD = 2.10; 95% CI = −1.31, 5.52; P = 0.23) of CKD patients.
Conclusion
Our results highlighted that probiotic supplements exerted a statistically significant effect on urea levels in non‐dialysis CKD population, while no evidence suggested that probiotics possessed meaningful impacts on the reduction of uric acid, C‐reactive protein, creatinine and estimated glomerular filtration rate preservation of CKD population.
SUMMARY AT A GLANCE
The effects of probiotic supplements on chronic kidney disease (CKD) progression were evaluated. The authors report a significant effect on reducing urea levels in non‐dialysis CKD population, whereas no significant impact was observed on uric acid, C‐reactive protein, creatinine and estimated glomerular filtration rate.
BackgroundSocioeconomic status (SES) has long been conjectured to be associated with the incidence and progression of chronic kidney disease (CKD), but few studies have examined this quantitatively. ...This meta-analysis aims to fill this gap.MethodsA systematic literature review was performed using Medline and EMBASE to identify observational studies on associations between SES and incidence and progression of CKD, published between 1974 and March 2017. Individual results were meta-analysed using a random effects model, in line with Meta-analysis of Observational Studies in Epidemiology guidelines.ResultsIn total, 43 articles met our inclusion criteria. CKD prevalence was associated with several indicators of SES, particularly lower income (OR 1.34, 95% CI (1.18 to 1.53), P<0.001; I2=73.0%, P=0.05); lower education (OR 1.21, 95% CI (1.11 to 1.32), P<0.001; I2=45.20%, P=0.034); and lower combined SES (OR 2.18, 95% CI (1.64 to 2.89), P<0.001; I2=0.0%, P=0.326). Lower levels of income, occupation and combined SES were also significantly associated with progression to end-stage renal disease (risk ratio (RR) 1.24, 95% CI (1.12 to 1.37), P<0.001; I2=66.6%, P=0.006; RR 1.05, 95% CI (1.01 to 1.09), P=0.012; I2=0.0%, P=0.796; and RR 1.39, 95% CI (1.09 to 1.79), P=0.009; I2=74.2%, P=0.009). Subgroup analyses generally confirmed these results, except in a few cases, such as an inverse association related to particular socioeconomic backgrounds and where results were adjusted by more disease-related risk factors.ConclusionLower income was most closely associated with prevalence and progression of CKD, and lower education was significantly associated with its prevalence. Evidence for other indicators was inconclusive.
Fatty acid‐binding protein 4 (FABP4) has been confirmed to be involved in the pathogenesis of ischaemia/reperfusion‐ and rhabdomyolysis‐induced acute kidney injury (AKI), and targeting inhibition of ...FABP4 might be a potential strategy for AKI. Cisplatin as a commonly used cancer chemotherapeutic drug possessed a dose‐limited side effect of nephrotoxicity. However, whether FABP4 inhibition exerted a favourable renoprotection against cisplatin‐induced AKI and the involved mechanisms remained unknown. In the study, cisplatin‐injected mice developed severe AKI symptom as indicated by renal dysfunction and pathological changes, companied by the high expression of FABP4 in tubular epithelial cells. Selective inhibition of FABP4 by BMS309403 at 40 mg/kg/d for 3 days and genetic knockout of FABP4 significantly attenuated the serum creatinine, blood urea nitrogen level and renal tubular damage. Mechanistically, cisplatin injection induced the increased apoptosis and regulated the corresponding protein expression of BCL‐2, BCL‐XL, BAX, cleaved caspase 3 and caspase 12 in the injured kidney tissues. Cisplatin also triggered multiple signal mediators of endoplasmic reticulum (ER) stress including double‐stranded RNA‐activated protein kinase‐like ER kinase, activating transcription factor‐6 and inositol‐requiring enzyme‐1 pathway, as well as CHOP, GRP78 and p‐JNK proteins in the kidneys. Oral administration of BMS309403 significantly reduced the number of renal TUNEL‐positive apoptotic cells. Knockout of FABP4 and BMS309403 notably improved ER stress‐related apoptotic responses. In summary, pharmacological and genetic inhibition of FABP4 modulated apoptosis via the inactivation of ER stress in the tubular epithelial cells of cisplatin‐induced AKI.
Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that ...histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.
The study aimed to evaluate the efficacy of the combination of CPP-ACP and fluorides compared with fluorides monotherapy on patients with early caries lesions. The Medline, Embase and Cochrane ...databases up to August 2017 were scanned, with no restrictions. Studies satisfied the guideline of randomised controlled trials (RCTs), the patients with early caries lesions and data considering the efficacy of fluorides and CPP-ACP versus fluorides alone were selected. There was no language restriction during the literature search process, however, only papers in English or Chinese were included during the selection process. Outcome variables include laser fluorescence, quantitative light-induced fluorescence, lesion area and visual inspection scores. Mean differences were calculated during the data extraction process. Ten studies including 559 patients were selected in the meta-analysis. Fluorides combined with CPP-ACP achieved the same efficacy for early caries lesions on smooth surfaces compared with fluorides monotherapy (mean difference: -13.90, 95% confidence interval: -39.25, 11.46, P = 0.28), and the combination treatment showed significantly better efficacy than fluorides monotherapy for occlusal early caries lesions (mean difference: -21.02, 95% confidence interval: -27.94, -14.10, P<0.01). However, further well-designed studies are still needed.
Background
The reported association between individual indicators of socioeconomic status (SES) and mortality in dialysis patients was inconsistent in previous studies. We performed a meta-analysis ...to identify the association between SES and mortality of dialysis population.
Methods
The meta-analysis was conducted in accordance with MOOSE guidelines. Cohorts evaluating the association between SES indicators (income, education and occupation) and mortality in dialysis patients were included. Random-effects models were used to pool the adjusted relative risk (RR) from individual studies. Heterogeneity was assessed by Cochrane’s
Q
and the
I
2
statistic. Subgroup analyses and sensitivity analyses were performed to identify sources of heterogeneity and to evaluate the robustness of findings.
Results
Fourteen studies were finally included. In hemodialysis patients, increased mortality was associated with lower level of income (RR = 1.08, 95%CI 1.01–1.16,
P
= 0.035;
I
2
= 87.9%,
P
< 0.001) and occupation (RR = 1.63, 95%CI 1.11–2.38,
P
= 0.013;
I
2
= 0.0%,
P
= 0.601). However, no significant association was identified for education (RR = 1.43, 95%CI 0.92–2.25;
P
= 0.112;
I
2
= 68.3%,
P
= 0.001). In patients receiving peritoneal dialysis, lower level of income (RR = 1.80, 95%CI 1.12–2.88,
P
= 0.015;
I
2
= 75.9%,
P
= 0.042), education (RR = 1.27, 95%CI 1.13–1.43,
P
< 0.001;
I
2
= 0.0%,
P
= 0.684), and occupation (RR = 3.42, 95% CI 1.35–8.70,
P
= 0.010) were risk factors for increased mortality. Subgroup analysis showed the association between SES indicators and mortality in hemodialysis differed according to geographic locations and study designs.
Conclusion
Lower SES (measured by income, education, and occupation) tends to be associated with higher mortality in patients receiving maintenance dialysis. But the magnitude of the associations varied for different individual indicators of SES.
Acute kidney injury (AKI) is a multifactorial disease of various aetiologies. Aryl hydrocarbon receptor (AhR) is a ligand‐activated transcription factor that responds to ligands to induce or repress ...gene expressions, thereby regulating a diverse spectrum of biological or pathophysiologic effects. However, the effect of AhR on AKI remains unknown. A single intraperitoneal injection of 50% glycerol was performed to induce rhabdomyolysis in C57BL/6J mice. The bilateral renal pedicles were occluded for 30 minutes and then removed to stimulate renal I/R injury. 6‐formylindolo3,2‐bcarbazole (FICZ), a photo‐oxidation product of tryptophan with a high affinity for AhR, was used. The in vitro study was performed on HK‐2 cells. Ferrous myoglobin and FICZ was dissolved in the medium in different cell groups. Treatment with AhR agonist FICZ significantly alleviated the elevation of serum creatinine and urea in AKI. AKI modelling‐induced renal damage was attenuated by FICZ. AhR mainly expressed in proximal tubular cells and could be activated by FICZ administration. Meanwhile, AKI triggered the production of pro‐inflammatory cytokines in injured kidneys, while FICZ inhibited their expressions. Furthermore, FICZ effectively reversed cell apoptosis in AKI models. Mechanistically, AKI stimulated the activation of NF‐κB and JNK pathways in the kidneys, while FICZ significantly suppressed these corresponding protein expressions. For the in vitro study, FICZ also inhibited inflammation and apoptosis in myoglobin or H/R‐stimulated HK‐2 cells. In summary, agonism of AhR by FICZ alleviated rhabdomyolysis and I/R‐induced AKI. FICZ inhibited inflammation and apoptosis via suppressing NF‐κB and JNK pathways in proximal tubular cells.
PDF
