Weekly pattern of dialysis unit blood pressure is a promising marker for prognosis evaluation in hemodialysis population.

BACKGROUND: Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS: We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS: One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS: Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.

Urinary small extracellular vesicles derived CCL21 mRNA as biomarker linked with pathogenesis for diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. METHODS: Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. RESULTS: The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. CONCLUSIONS: Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.

Risk factors for calciphylaxis in Chinese hemodialysis patients: a matched case-control study.

INTRODUCTION: Calciphylaxis is a rare but potentially fatal disease commonly occurred in dialysis patients. Despite some previous studies on risk factors for calciphylaxis, there is still a lack of data from Chinese population. METHODS: The retrospective matched case-control study about calciphylaxis was performed in Zhongda Hospital affiliated to Southeast University. The case group involved 20 hemodialysis patients who were newly diagnosed with calciphylaxis from October 2017 to December 2018. The 40 noncalciphylaxis patients undergoing dialysis with the same age and duration of dialysis were randomly selected as controls. RESULTS: Most of calciphylaxis patients were male and elderly, while overweight people were more susceptible to the disease. Although incidence of secondary hyperparathyroidism was higher in calciphylaxis patients, the differences in duration of elevated serum intact parathyroid hormone (iPTH) and its highest value did not reach statistical significance compared with controls. No significant difference in warfarin therapy was discernible between two groups. The univariate regression analysis indicated that male, score of use of activated vitamin D and its analogues, corrected serum calcium level, serum phosphate, Ca × P product, iPTH, albumin, and alkaline phosphatase (ALP) level were significantly associated with calciphylaxis. Elevated levels of serum phosphate (OR 4.584, p = 0.027) and ALP (OR 1.179, p = 0.036), decreased level of serum albumin (OR 1.330, p = 0.013) were independent risk factors after multivariate analysis. CONCLUSION: This is the first report of risk factors associated with calciphylaxis in China. Increased levels of serum phosphate and ALP, decreased level of serum albumin were vital high-risk factors for calciphylaxis in Chinese hemodialysis population.

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.

MicroRNA26a inhibits cisplatin-induced renal tubular epithelial cells apoptosis through suppressing the expression of transient receptor potential channel 6 mediated dynamin-related protein 1.

Acute kidney injury (AKI) is a common adverse reaction of the anticancer drug. Among these chemotherapeutic agents, cisplatin, an effective chemotherapeutic drug, is extensively applied to the treatment of solid tumours, yet various adverse reactions, especially AKI, often limit their use. However, the pathogenesis of AKI caused by cisplatin remains poorly clarified. Therefore, we tested whether microRNAs, which have been certified as key regulators of disease are involved in this process. AKI mouse and HK2 cells were treated with cisplatin. Annexin V/PI staining and cleaved caspase-3 were used to assess apoptosis. Western blot analyses and qRT-PCR were used to evaluate the protein and mRNA level of TRPC6 and DRP1. miR-26a was remarkably decreased in cisplatin-induced AKI and in cisplatin co-cultured HK2 cells. Furthermore, we used a miR-26a mimics in vitro and found that apoptosis was alleviated than that in the control cells. We further verified that miR-26a protected against cisplatin-induced cell apoptosis by acting on transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamin-related protein 1 (DRP1), thus inhibited the mitochondrial apoptosis pathway. Therefore, the study unveiled that miR-26a/TRPC6/DRP1 is a novel protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related renal injury. SIGNIFICANCE OF THE STUDY: Our study found that miR-26a was significantly downregulated during cisplatin-induced AKI and during cisplatin co-cultured HK2 cells. Further, in vitro we used miR-26a mimic to intervene cells and found that apoptosis alleviated compared with control group. We further verified that miR-26a protected cisplatin-induced apoptosis by target transient receptor potential channel 6 (TRPC6) which can regulate the expression of dynamic-related protein 1 (DRP1) and inhibit the mitochondrial apoptosis pathway. Thus, miR-26a/TRPC6/DRP1 is a new protective pathway in cisplatin-induced AKI and may be targeted for the prevention and treatment of drug-related acute kidney injury.

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.

Artemisinin attenuates tubulointerstitial inflammation and fibrosis via the NF-κB/NLRP3 pathway in rats with 5/6 subtotal nephrectomy.

Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway.

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.

Bartter syndrome type III with only a synonymous mutation of the CLCNKB gene
.

Bartter syndrome (BS), a rare autosomal recessive disorder affecting renal tubular potassium handling, is characterized by hypokalemia, metabolic alkalosis, and renal salt wasting. In this report, we describe an adult patient with longstanding clinical symptoms of fatigue, polyuria, polydipsia, mental retardation, and physical dysplasia along with hypokalemia and metabolic alkalosis as laboratory findings. With these clinical symptoms, a patient can be diagnosed with BS type III. Renal biopsy and genetic testing were performed for further confirmation of the diagnosis, revealing renin granular deposits in the juxtaglomerular apparatus (JA) with JA hyperplasia. DNA sequencing detected a heterozygous synonymous mutation, c.1140G>A, in exon 12 of the CLCNKB gene, which could be traced back to a heterozygous synonymous mutation in the patient's mother, who does not have BS.

A rat model of SHPT with bone abnormalities in CKD induced by adenine and a high phosphorus diet.

The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT.

Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease.

BACKGROUND/AIMS: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. METHODS: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. RESULTS: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. CONCLUSION: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets.

Elevated PTH induces endothelial-to-chondrogenic transition in aortic endothelial cells.

Previous studies have shown that increased parathyroid hormone (PTH) attributable to secondary hyperparathyroidism in chronic kidney disease accelerates the arteriosclerotic fibrosis and calcification. Although the underlying mechanisms remain largely unknown, endothelial cells (ECs) have recently been demonstrated to participate in calcification in part by providing chondrogenic cells via the endothelial-to-mesenchymal transition (EndMT). Therefore, this study aimed to investigate whether elevated PTH could induce endothelial-to-chondrogenic transition in aortic ECs and to determine the possible underlying signaling pathway. We found that treatment of ECs with PTH significantly upregulated the expression of EndMT-related markers. Accordingly, ECs treated with PTH exhibited chondrogenic potential. In vivo, lineage-tracing model-subjected mice with endothelial-specific green fluorescent protein fluorescence to chronic PTH infusion showed a marked increase in the aortic expression of chondrocyte markers, and confocal microscopy revealed the endothelial origin of cells expressing chondrocyte markers in the aorta after PTH infusion. Furthermore, this in vitro study showed that PTH enhanced the nuclear localization of ß-catenin in ECs, whereas ß-catenin siRNA or DKK1, an inhibitor of ß-catenin nuclear translocation, attenuated the upregulation of EndMT-associated and chondrogenic markers induced by PTH. In summary, our study demonstrated that elevated PTH could induce the transition of ECs to chondrogenic cells via EndMT, possibly mediated by the nuclear translocation of ß-catenin.

Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation.

Albuminuria contributes to the development and progression of chronic kidney disease by inducing tubulointerstitial inflammation (TI) and fibrosis. However, the exact mechanisms of TI in response to albuminuria are unresolved. We previously demonstrated that NLRP3 and inflammasomes mediate albumin-induced lesions in tubular cells. Here, we further investigated the role of endocytic receptors and lysosome rupture in NLRP3 inflammasome activation. A murine proteinuric nephropathy model was induced by albumin overload as described previously. The priming and activation signals for inflammasome complex formation were evoked simultaneously by albumin excess in tubular epithelial cells. The former signal was dependent on a albumin-triggered NF-κB pathway activation. This process is mediated by the endocytic receptor, megalin and cubilin. However, the silencing of megalin or cubilin inhibited the albumin-induced NLRP3 signal. Notably, subsequent lysosome rupture and the corresponding release of lysosomal hydrolases, especially cathepsin B, were observed in tubular epithelial cells exposed to albumin. Cathepsin B release and distribution are essential for NLRP3 signal activation, and inhibitors of cathepsin B suppressed the NLRP3 signal in tubular epithelial cells. Taken together, our findings suggest that megalin/cubilin and lysosome rupture are involved in albumin-triggered tubular injury and TI. This study provides novel insights into albuminuria-induced TI and implicates the active control of albuminuria as a critical strategy to halt the progression of chronic kidney disease.

Interleukin-1ß mediates high glucose induced phenotypic transition in human aortic endothelial cells.

BACKGROUND: Previous studies have shown that high glucose (HG) induced endothelial cell (EC) damage via a phenotypic transition of EC. There is increasing evidence suggesting the role of inflammatory cytokines in mediated HG-induced EC damage. However, little is known about the potential role of interleukin-1ß (IL-1ß) in the process. The aim of present study was to investigate whether IL-1ß mediated HG-induced phenotypic transition in human aortic endothelial cells (HAECs) and to determine the possible underlying mechanism. METHODS: Primary HAECs were exposed to normal glucose (NG, 5.5 nM), high glucose (HG,30 nM), IL-1ß (10 ng/ml), HG + IL-1ß (10 ng/ml) and HG + anti-IL-1ß antibodies (1000 ng/ml) or HG + IL-1ß small interfering RNA (siRNA). Pathological changes were investigated using confocal microscopy and electron microscopy. Confocal microscopy was performed to detect the co-expression of CD31 and fibroblast specific protein 1 (FSP1). To study the effect of protein kinase C-ß (PKCß) activation on IL-1ß in HAECs, HAECs were stimulated with 30 nM PMA (PKCß activator) and 0.3 µM PKCß inhibition (LY317615) for 48 h in the NG or HG group. The expressions of PKCß and IL-1ß were detected by RT-PCR and Western blot. And the concentration of IL-1ß in the supernatant of HAECs was measured by ELISA. The expressions of FSP1, a-SMA and CD31 were detected by Western blot. RESULTS: It was shown that the HG resulted in significant increase in the expressions of PKCß and IL-1ß in dose-and time-dependent manners. The HG or exogenous IL-1ß alone inhibited the expression of CD31 and markly increased the expressions of FSP1 and α-SMA. Furthermore, we observed that the HG and IL-1ß synergistically increased FSP1 and a-SMA expressions compared with the HG or IL-1ß alone group (P < 0.05). Confocal microscopy revealed a colocalization of CD31 and FSP1 and that some cells acquired spindle-shaped morphologies and a loss of CD31 staining. Electron microscopy showed that the HG resulted in the increased microfilamentation and a roughened endoplasmic reticulum structure in the cytoplasm. However, the changes above were attenuated by the intervention of anti-IL-1ß antibodies or IL-1ß siRNA (P < 0.05). In addition, the PMA induced the expressions of PKCß and IL-1ß in HAECs. The PKCß activation may mediate the effect of the HG on IL-1ß production, which could be attenuated by the PKCß selective inhibitor (LY317615) (P < 0.05). CONCLUSIONS: Our findings suggested that HG-induced phenotypic transition of HAECs might require IL-ß activation via the PKCß pathway.

Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition.

AIM: Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT. METHODS: Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs. RESULTS: In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner. CONCLUSION: These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.

The characteristics and mortality risk factors for acute kidney injury in different age groups in China-a cross sectional study.

AIM: Age is an independent risk factor for acute kidney injury (AKI). The causes and outcomes of AKI in children, middle-aged, and older patients are different. The objective of this country-based study was to identify the characteristics and mortality factors for AKI in different age groups in China. METHODS: Using data from 374,286 adult patients (≥18 years) admitted to 44 study hospitals, we investigated the characteristics and mortality risk factors for AKI in four different age groups: 18-39 years of age, 40-59 years of age, 60-79 years of age, and ≥80 years of age. The identification criteria for AKI included the 2012 KDIGO AKI definition and an expanded criterion. RESULTS: The country-based survey included 7604 AKI patients (7604/374,286, 2.03%). The proportions of AKI in the four age groups were 11.52%, 30.79%, 41.03%, and 16.66%, respectively. In any age group, the patients with AKI stage 1 were the majority (43.4%, 42.4%, 46.4%, and 52.2%, respectively), and the most common classification of AKI was pre-renal AKI (44.3%, 51.3%, 52.3%, and 56.4%, respectively). The higher AKI peak stage occurred for the in-hospital mortality factors for AKI in all age groups; except for the AKI stage 2 patients in the 18-39 age group. CONCLUSION: The characteristics and mortality factors for AKI vary by age in China. Elderly patients were the primary population with AKI, and the most common type of AKI was pre-renal AKI. Special caution should be taken to the old population in hospitalized patients to prevent the pre-renal AKI.

Involvement of endoplasmic reticulum stress in angiotensin II-induced NLRP3 inflammasome activation in human renal proximal tubular cells in vitro.

AIM: NLRP3 inflammasome plays an important role in renal injury and may be a therapeutic target in the treatment of patients with progressive chronic kidney disease. In this study we investigated whether angiotensin II (Ang II)-induced NLRP3 inflammasome activation was linked to endoplasmic reticulum stress (ERS) in human renal proximal tubular cells in vitro. METHODS: Human kidney proximal epithelial cells (HK-2) were pretreated with telmisartan or 4-PBA, and then treated with Ang II. The expression levels of mRNAs and proteins related to NLRP3 inflammasomes and ERS was examined by real-time PCR, Western blot and immunofluorescence. RESULTS: Treatment with Ang II (10, 100, and 1000 nmol/L) increased the expression of the inflammasome markers NLRP3 and ASC, as well as caspase-1, IL-1ß, and IL-18 in dose- and time-dependent manners with peak levels detected at 100 nmol/L and 12 h. Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1ß, and IL-18 were significantly reduced by pretreatment with telmisartan (1 µmol/L). Immunofluorescence studies showed that Ang II increased the expression of NLRP3 and ASC, which was inhibited by telmisartan. Furthermore, Ang II treatment increased the expression of ERS markers GRP78 and p-eIF2α in dose- and time-dependent manners, which was significantly reduced by telmisartan. Moreover, Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1ß, and IL-18 were significantly inhibited by pretreatment with the ERS inhibitor 4-PBA (5 mmol/L). CONCLUSION: Ang II treatment induces NLRP3 inflammasome activation in HK-2 cells in vitro and ER stress is involved in this process, which may represent a new mechanism for the renal rennin-angiotensin system to induce tubulointerstitial inflammation.

The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis.

To date, case-control studies on the association between a single-nucleotide polymorphism (SNP), rs2268388, in the acetyl-coenzyme A carboxylase beta (ACACB) gene and diabetic nephropathy have provided controversial results. To clarify the effect of rs2268388 on the risk of diabetic nephropathy, a meta-analysis of all case-control studies was performed. The fixed effects and random effects models showed that the C allele was associated with a decreased susceptibility risk of diabetic nephropathy compared with the T allele among Caucasian patients with diabetes. The contrast of the recessive model produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between rs2268388 and diabetic nephropathy among Caucasian patients with diabetes.

A meta-analysis of MTRR A66G polymorphism and colorectal cancer susceptibility.

PURPOSE: A meta-analysis was performed to determine the association between MTRR A66G polymorphism and colorectal cancer (CRC) susceptibility. METHODS: Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between MTRR A66G polymorphism and CRC susceptibility. RESULTS: A total of 6020 cases and 8317 controls in 15 studies were pooled together for evaluation of the overall association between MTRR A66G polymorphism and susceptibility of CRC. The allele model (G vs A: p=0.01; OR=1.07, 95% CI=1.02-1.12), and homozygous model (GG vs AA: p=0.006; OR=1.15, 95% CI=1.04-1.28) showed increased risk for CRC development. Similarly, the dominant model (GG+GA vs AA: p=0.04; OR=1.11, 95% CI=1.01-1.22) and the recessive model (GG vs GA+AA: p=0.04; OR=1.08, 95% CI=1.00-1.17) showed increased risk for CRC development. In the analysis stratified by ethnicity (Caucasian and East Asian), significant associations were found between MTRR A66G polymorphism and susceptibility to CRC among Caucasians. CONCLUSION: Our pooled data suggest an association between MTRR A66G polymorphism and CRC susceptibility among Caucasians.

Nuclear translocation of ß-catenin mediates the parathyroid hormone-induced endothelial-to-mesenchymal transition in human renal glomerular endothelial cells.

Emerging evidence shows that increased parathyroid hormone (PTH) accelerates endothelial injury and subsequent organ fibrosis. Although the underlying mechanisms remain largely unknown, the endothelial-to-mesenchymal transition (EndMT) has recently been demonstrated to be a crucial event during fibrotic disorders. Therefore, the present study aimed to investigate whether elevated PTH could induce EndMT in primary human renal glomerular endothelial cells (GECs) and to determine the possible underlying signaling pathway. The expression of EndMT-related markers was determined by real-time PCR, Western blotting, and confocal microscopy. The results showed that PTH receptor (PTHR) was expressed in GECs and its expression was decreased by increasing concentration of PTH. Moreover, PTH significantly inhibited the expression of endothelial marker CD31 and increased the expression of mesenchymal markers FSP1 and α-SMA in concentration- and time-dependent manners. Confocal microscopy revealed an increasing overlap of CD31 with FSP1 in some GECs after PTH treatment. The expression of type I collagen was upregulated by PTH. Furthermore, PTH enhanced the nuclear ß-catenin protein levels, and decreased cytoplasmic ß-catenin expression in GECs was observed. In contrast, DKK1, an inhibitor of ß-catenin nuclear translocation, attenuated such changes in EndMT-related markers induced by PTH. In summary, these data demonstrated that elevated PTH-induced EndMT in human GECs might be partially mediated by the nuclear translocation of ß-catenin.