KIM-1 augments hypoxia-induced tubulointerstitial inflammation through uptake of small extracellular vesicles by tubular epithelial cells.

Tubular epithelial cells (TECs) exposed to hypoxia incite tubulointerstitial inflammation (TII), while the exact mechanism is unclear. In this study, we identified that hypoxia evoked tubule injury as evidenced by tubular hypoxia-inducible factor-1α and kidney injury molecule-1 (KIM-1) expression and that renal small extracellular vesicle (sEV) production was increased with the development of TII after ischemia-reperfusion injury (IRI). Intriguingly, KIM-1-positive tubules were surrounded by macrophages and co-localized with sEVs. In vitro, KIM-1 expression and sEV release were increased in hypoxic TECs and the hypoxia-induced inflammatory response was ameliorated when KIM-1 or Rab27a, a master regulator of sEV secretion, was silenced. Furthermore, KIM-1 was identified to mediate hypoxic TEC-derived sEV (Hypo-sEV) uptake by TECs. Phosphatidylserine (PS), a ligand of KIM-1, was present in Hypo-sEVs as detected by nanoflow cytometry. Correspondingly, the inflammatory response induced by exogenous Hypo-sEVs was attenuated when KIM-1 was knocked down. In vivo, exogenous-applied Hypo-sEVs localized to KIM-1-positive tubules and exacerbated TII in IRI mice. Our study demonstrated that KIM-1 expressed by injured tubules mediated sEV uptake via recognizing PS, which participated in the amplification of tubule inflammation induced by hypoxia, leading to the development of TII in ischemic acute kidney injury.

The clinical evaluation of the triglyceride-glucose index as a risk factor for coronary artery disease and severity of coronary artery stenosis in patients with chronic kidney disease.

INTRODUCTION: Insulin resistance (IR) plays an important role in the occurrence and development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). The triglyceride-glucose (TyG) index is a simple and effective tool to evaluate IR. This study aimed to evaluate the association of the TyG index with coronary artery disease (CAD) and the severity of coronary artery stenosis (CAS) in nondialysis patients with stages 3-5 CKD. METHODS: Nondialysis patients with stages 3-5 CKD who underwent the first coronary angiography at Zhongda Hospital affiliated with Southeast University from August 2015 to January 2017 were retrospectively analyzed. CAS was measured by coronary angiography, and the CAS score was calculated as the Gensini score. Logistic regression analysis was used to determine the related factors of CAD and severe CAS. RESULTS: A total of 943 patients were enrolled in this cross-sectional study and 720 (76.4%) of these patients were diagnosed with CAD. The TyG index in the CAD group (7.29 ± 0.63) was significantly higher than that in the non-CAD group (7.11 ± 0.61) (p < 0.001). Multivariate logistic regression analysis showed that a higher TyG index was an independent risk factor for CAD in CKD patients after adjusting for related confounding factors (OR = 2.865, 95% CI 1.681-4.885, p < 0.001). Patients in the CAD group were divided into three groups according to the Gensini integral quantile level. Multivariate logistic regression analysis showed that the TyG index was an independent related factor for severe CAS after adjusting for relevant confounding factors (p < 0.001). CONCLUSIONS: The TyG index is associated with CAD and the severity of CAS in patients with nondialysis stages 3-5 CKD. A higher TyG index is an independent factor for CAD and severe CAS.

Fibroblast growth factor 21 predicts arteriovenous fistula functional patency loss and mortality in patients undergoing maintenance hemodialysis.

BACKGROUND: Arteriovenous fistula (AVF) dysfunction is a common complication in patients undergoing maintenance hemodialysis (MHD). Elevated serum levels of fibroblast growth factor 21 (FGF21) are associated with atherosclerosis and cardiovascular mortality. However, its association with vascular access outcomes remains elusive. The present study evaluated the relationship of serum FGF21 levels with AVF dysfunction and all-cause mortality in patients undergoing MHD. METHODS: We included patients undergoing MHD using AVF from January 2018 to December 2019. FGF21 concentration was detected using enzyme-linked immunosorbent assay. Patients were followed up to record two clinical outcomes, AVF functional patency loss and all-cause mortality. The follow-up period ended on April 30, 2022. RESULTS: Among 147 patients, the mean age was 58.49 ± 14.41 years, and the median serum level of FGF21 was 150.15 (70.57-318.01) pg/mL. During the median follow-up period of 40.83 months, the serum level of FGF21 was an independent risk factor for AVF functional patency loss (per 1 pg/mL increase, HR 1.002 [95% CI: 1.001-1.003, p = 0.003]). Patients with higher serum levels of FGF21 were more likely to suffer from all-cause mortality (per 1 pg/mL increase, HR 1.002 [95% CI: 1.000-1.003, p = 0.014]). The optimal cutoffs for FGF21 to predict AVF functional patency loss and all-cause mortality in patients undergoing MHD were 149.98 pg/mL and 146.43 pg/mL, with AUCs of 0.701 (95% CI: 0.606-0.796, p < 0.001) and 0.677 (95% CI: 0.595-0.752, p = 0.002), respectively. CONCLUSIONS: Serum FGF21 levels were an independent risk factor and predictor for AVF functional patency loss and all-cause mortality in patients undergoing MHD.

Quercetin alleviates tubulointerstitial inflammation by inhibiting exosomes-mediated crosstalk between tubular epithelial cells and macrophages.

BACKGROUND: Tubulointerstitial inflammation (TII) is a critical pathological feature of kidney disease leading to renal fibrosis, and its treatment remains a major clinical challenge. We sought to explore the role of quercetin, a potential exosomes inhibitor, in exosomes release and TII. METHODS: The effects of quercetin on exosomes release and TII were examined by two TII mouse models: the unilateral ureteral obstruction (UUO) models and the LPS-induced mouse models. In vitro, exosomes-mediated crosstalk between tubular epithelial cells (TECs) and macrophages was performed to investigate the mechanisms by which quercetin inhibited exosomes and TII. RESULTS: In this study, we found that exosomes-mediated crosstalk between TECs and macrophages contributed to the development of TII. In vitro, exosomes released from LPS-stimulated TECs induced increased expression of inflammatory cytokines and fibrotic markers in Raw264·7 cells and vice versa. Interestingly, heat shock protein 70 (Hsp70) or Hsp90 proteins could control exosomes release from TECs and macrophages both in vivo and in vitro. Importantly, quercetin, a previously recognized heat shock protein inhibitor, could significantly reduce exosomes release in TII models by down-regulating Hsp70 or Hsp90. Quercetin abrogated exosomes-mediated intercellular communication, which attenuated TII and renal fibrosis accordingly. CONCLUSION: Quercetin could serve as a novel strategy for treatment of tubulointerstitial inflammation by inhibiting the exosomes-mediated crosstalk between tubules and macrophages.

Tubular-specific CDK12 knockout causes a defect in urine concentration due to premature cleavage of the slc12a1 gene.

Cyclin-dependent kinase 12 (CDK12) plays a critical role in regulating gene transcription. CDK12 inhibition is a potential anticancer therapeutic strategy. However, several clinical trials have shown that CDK inhibitors might cause renal dysfunction and electrolyte disorders. CDK12 is abundant in renal tubular epithelial cells (RTECs), but the exact role of CDK12 in renal physiology remains unclear. Genetic knockout of CDK12 in mouse RTECs causes polydipsia, polyuria, and hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced Na-K-2Cl cotransporter 2 (NKCC2) levels in the kidney. In addition, CKD12 knockout causes an increase in Slc12a1 (which encodes NKCC2) intronic polyadenylation events, which results in Slc12a1 truncated transcript production and NKCC2 downregulation. These findings provide novel insight into CDK12 being necessary for maintaining renal homeostasis by regulating NKCC2 transcription, which explains the critical water and electrolyte disturbance that occurs during the application of CDK12 inhibitors for cancer treatment. Therefore, there are safety concerns about the clinical use of these new anticancer drugs.

PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm.

PAX6 is essential for neural retina (NR) and forebrain development but how PAX6 instructs NR versus forebrain specification remains unknown. We found that the paired-less PAX6, PAX6D, is expressed in NR cells during human eye development and along human embryonic stem cell (hESC) specification to retinal cells. hESCs deficient for PAX6D failed to enter NR specification. Induced expression of PAX6D but not PAX6A in a PAX6-null background restored the NR specification capacity. ChIP-Seq, confirmed by functional assays, revealed a set of retinal genes and non-retinal neural genes that are potential targets of PAX6D, including WNT8B. Inhibition of WNTs or knocking down of WNT8B restored the NR specification capacity of neuroepithelia with PAX6D knockout, whereas activation of WNTs blocked NR specification even when PAX6D was induced. Thus, PAX6D specifies neuroepithelia to NR cells via the regulation of WNT8B.

Exploration of a new hepatitis a surveillance system in Beijing, China: based on molecular epidemiology.

BACKGROUND: The incidence of hepatitis A virus (HAV) infection is low in Beijing, China, but the risk of outbreaks still exists. It is difficult to identify possible sources of infection among sporadic cases based on a routine surveillance system. Therefore, a more effective surveillance system needs to be established. METHODS: The epidemiological data of hepatitis A were obtained from a routine surveillance system. Patients with HAV confirmed at the local hospitals were asked to complete a questionnaire that included additional case information and possible sources of infection. Serum and fecal specimens were also collected for testing HAV RNA by polymerase chain reaction. In addition, the 321-nucleotide segment of the VP1/2A junction region was sequenced to determine the HAV genotype. RESULTS: In 2019, 110 HAV cases were reported in Beijing, with an incidence rate of 0.51/100,000. 61(55.5%) of these patients were male. The greatest proportion of these patients were aged from 30 to 60 years. The rate was lower in suburban and rural areas compared to urban areas. Contaminated food consumption, particularly seafood consumption, was the primary potential source of infection. Among the 16 specimens of confirmed HAV cases that could be sequenced, 93.8% were HAV IA, and 6.3% were HAV IB. In addition, the samples collected from all HAV sequences in this investigation showed 89.4-100% nucleotide homology. Two groups (each with three sporadic cases) showed 100% nucleotide homology. The three sporadic cases in one group had the same possible source of infection: contaminated salad with raw vegetables and seafood. In the other group, the three sporadic cases did not have an epidemiological connection. CONCLUSIONS: In a low HAV prevalent area, such as in Beijing, incorporating molecular epidemiology into the routine surveillance system could help inform possible clusters of outbreaks and provide support for earlier control of HAV transmission. Nevertheless, increased sampling from detected cases and improved specimen quality are needed to implement such a system.

Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI.

BACKGROUND: AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. METHODS: We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. RESULTS: REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. CONCLUSIONS: A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

HIF-1α is transcriptionally regulated by NF-κB in acute kidney injury.

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

FIH-1-modulated HIF-1α C-TAD promotes acute kidney injury to chronic kidney disease progression via regulating KLF5 signaling.

Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg-1·d-1, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.

Autophagosome protects proximal tubular cells from aldosterone-induced senescence through improving oxidative stress.

Aldosterone exerts an enormous function on proximal tubular cells (PTC) senescence, which is a common pathomechanism contributing to renal dysfunction. Numerous studies have shown that oxidative stress is deeply involved in the pathophysiologic processes of chronic kidney diseases. The study aims to investigate whether autophagy could regulate the process of senescence through oxidative stress in PTC both in vivo and ex vivo. Our results suggested that aldosterone treatment increased the senescence and oxidative stress as evidenced by increased percent of SA-ß-Gal positive cells, reactive oxygen species level, expression of NADPH oxidase 4 (NOX4) rather than NOX2, and the up-regulation of p21 in cultured PTC. Furthermore, the alternation of the expression of p62 and LC3-II/LC3-I demonstrated that aldosterone treatment remarkably influenced autophagic flux. NOX4 siRNA treatment or autophagy induction with rapamycin reduced the oxidative stress and senescence in aldosterone-induced PTC. On the contrary, inhibition of autophagy with chloroquine worsened these changes. Similar results were further confirmed in vivo. Our results suggested that autophagy may become a realistic therapeutic strategy against aldosterone-induced PTC injury via improving oxidative stress.

Association between serum elastin-derived peptides and abdominal aortic calcification in peritoneal dialysis patients: a cross-sectional study.

BACKGROUND: Peritoneal dialysis (PD) patients experience accelerated arterial aging, which is characterized by elastin degradation. Elastin-derived peptides (EDPs) are direct products of elastin fragmentation. This study tried to explore the association between serum EDPs and abdominal aortic calcification (AAC) in PD patients. METHODS: Serum levels of EDPs were analyzed in 126 eligible PD patients and 30 controls. PD patients were grouped according to the annularity of AAC evaluated by an abdominal computed tomography (CT) scan. Serum EDPs were analyzed in relation to the presence of AAC or severe AAC in PD patients by logistic regression analysis. RESULTS: Serum EDPs in PD patients were significantly higher than age-matched controls. In 126 PD patients, higher EDPs was associated with greater risk of present AAC (OR = 1.056, 95%CI 1.010-1.103) and severe AAC (OR = 1.062, 95%CI 1.004-1.123). A combination of EDPs substantially improved the accuracy of diagnostic performance for AAC and severe AAC. CONCLUSIONS: EDPs can predict the presence and extent of AAC in PD patients, indicating its possible role to recognize PD patients at risk for AAC and severe AAC.

The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

Importance of Wintertime Anthropogenic Glyoxal and Methylglyoxal Emissions in Beijing and Implications for Secondary Organic Aerosol Formation in Megacities.

Atmospheric glyoxal (GLY) and methylglyoxal (MGLY) are key precursors of secondary organic aerosol (SOA). However, anthropogenic emissions of GLY and MGLY and their contribution to surface GLY and MGLY concentrations, as well as the secondary organic aerosol (SOA) formation, are not well quantified. By developing an emission inventory of anthropogenic GLY and MGLY and improving the Community Multiscale Air Quality Model (CMAQ) with SOA formation from irreversible surface uptake of GLY and MGLY, as well as a precursor-origin resolved technique, we quantified the source contributions of GLY and MGLY and their impact on wintertime SOA formation in Beijing, China. The total emissions of GLY and MGLY in Beijing in 2017 are 1.1 × 104 kmol and 7.0 × 103 kmol, respectively. Anthropogenic primary emissions are found to be the dominant contributor to wintertime GLY and MGLY concentrations (∼74% for GLY and ∼63% for MGLY). Anthropogenic primary emissions of GLY and MGLY contributes to 30% of GLY/MGLY SOA daily average concentration and accounts for up to 45% of nighttime GLY/MGLY SOA in winter. The study suggests that the anthropogenic GLY and MGLY emissions, mainly from gasoline vehicles and cooking, are important for SOA formation and shall be strictly controlled in Chinese megacities.

Dopamine D1 receptor agonist A68930 attenuates acute kidney injury by inhibiting NLRP3 inflammasome activation.

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.

Quantitative determination of rifampicin in aquatic products by stable isotope-dilution high liquid chromatography-tandem mass spectrometry.

Rifampicin is a semi-synthetic broad-spectrum antibiotic obtained from rifamycin B. It is one of the most effective first-line antituberculosis drugs and is widely used in clinical practice. In the present study, we describe a rapid and sensitive method for the determination of rifampin in aquatic products by stable isotope-dilution high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Samples were extracted with the acetonitrile, degreased by hexane, and then concentrated by nitrogen blowing. After separation using a C18 column with a mixture of acetonitrile and water as mobile phase, it was determined by HPLC-MS/MS using the stable isotope-dilution calibration method. The performance of our method was validated. The limit of detection was 0.25 µg kg-1 and the limit of quantification was 0.5 µg kg-1 . At the three spiked levels of 0.5, 1.0 and 5.0 µg kg-1 , the average recoveries of rifampicin in different aquatic products were between 75.28 and 107.6%, and the relative standard deviation ranged from 0.81 to 13.23%. This method was successfully applied for the determination of rifampin in different kinds of aquatic products and rifampicin residue was found in aquatic products obtained from markets in Beijing, China.

Effect of hypoxia-inducible factor-prolyl hydroxylase inhibitors on anemia in patients with CKD: a meta-analysis of randomized controlled trials including 2804 patients.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Overexpression of oncostatin M receptor regulates local immune response in glioblastoma.

Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL-6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations-counter (MCP-counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity-related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

Calcium-sensing receptor mediates interleukin-1ß-induced collagen expression in mouse collecting duct cells.

The mechanisms that underlie the profibrotic effect of interleukin (IL)-1ß are complicated and not fully understood. Recent evidence has suggested the involvement of the calcium-sensing receptor (CaSR) in tubular injury. Therefore, the current study aimed to investigate whether CaSR mediates IL-1ß-induced collagen expression in cultured mouse inner medullary collecting duct cells (mIMCD3) and to determine the possible downstream signaling effector. The results showed that IL-1ß significantly upregulated the expression of type I and III collagens in a concentration- and time-dependent manner. Moreover, CaSR was expressed in mIMCD3 cells, and its expression was increased by increasing the concentrations and times of IL-1ß treatment. Selective inhibitors (Calhex231 or NPS2143) or the siRNA of CaSR attenuated the enhanced expression of type I and III collagens. Furthermore, IL-1ß increased nuclear ß-catenin protein levels and decreased cytoplasmic ß-catenin expression in cells. In contrast, blockage of CaSR by the pharmacological antagonists or siRNA could partially attenuate such changes in the IL-1ß-induced nuclear translocation of ß-catenin. DKK1, an inhibitor of ß-catenin nuclear translocation, further inhibited the expression of type I and III collagens in cells treated with IL-1ß plus CaSR antagonist. In summary, these data demonstrated that IL-1ß-induced collagen I and III expressions in collecting duct cells might be partially mediated by CaSR and the downstream nuclear translocation of ß-catenin.

HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation.

Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1α modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1α expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1α in tubular epithelial cells was associated with selective shedding of microRNA-23a (miRNA-23a)-enriched exosomes in vivo and systemic inhibition of miRNA-23a prior to ischemia/reperfusion injury attenuated tubulointerstitial inflammation. In vitro, uptake of miRNA-23a-enriched exosomes by macrophages triggered their reprogramming into a pro-inflammatory state via suppression of the ubiquitin editor A20. To confirm the effect of miRNA-23a-containing exosomes on tubulointerstitial inflammation, we exposed tubular epithelial cells to hypoxic conditions to promote the release of miRNA-23a-containing exosomes. Injection of these miRNA-23a-enriched exosomes into uninjured renal parenchyma resulted in increased inflammatory infiltration in vivo. Taken together, our studies demonstrate that the HIF-1α-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosome-mediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation.