A decision support system for upper limb rehabilitation robot based on hybrid reasoning with RBR and CBR.

The rehabilitation robot can assist hemiplegic patients to complete the training program effectively, but it only focuses on helping the patient's training process and requires the rehabilitation therapists to manually adjust the training parameters according to the patient's condition. Therefore, there is an urgent need for intelligent training prescription research of rehabilitation robots to promote the clinical applications. This study proposed a decision support system for the training of upper limb rehabilitation robot based on hybrid reasoning with rule-based reasoning (RBR) and case-based reasoning (CBR). The expert knowledge base of this system is established base on 10 professional rehabilitation therapists from three different rehabilitation departments in Shanghai who are enriched with experiences in using desktop-based upper limb rehabilitation robot. The rule-based reasoning is chosen to construct the cycle plan inference model, which develops a 21-day training plan for the patients. The case base consists of historical case data from 54 stroke patients who underwent rehabilitation training with a desktop-based upper limb rehabilitation robot. The case-based reasoning, combined with a Random Forest optimized algorithm, was constructed to adjust the training parameters for the patients in real-time. The system recommended a rehabilitation training program with an average accuracy of 91.5%, an average AUC value of 0.924, an average recall rate of 88.7%, and an average F1 score of 90.1%. The application of this system in rehabilitation robot would be useful for therapists.

Cloning and functional verification of the CmHSP17.9 gene from chrysanthemum.

Small molecular heat shock proteins (sHSPs) belong to the HSP family of molecular chaperones. Under high-temperature stress, they can prevent the aggregation of irreversible proteins and maintain the folding of denatured proteins to enhance heat resistance. In this study, the CmHSP17.9-1 and CmHSP17.9-2 genes, which were cloned from chrysanthemum (Chrysanthemum×morifolium 'Jinba') by homologous cloning, had a complete open reading frame of 480 bp each, encoding 159 amino acids. The protein subcellular localization analysis showed that CmHSP17.9-1 and CmHSP17.9-2 were located in the cytoplasm and mostly aggregated in granules, especially around the nucleus. Real-time quantitative PCR (qRT-PCR) analysis showed that the relative expression level of the CmHSP17.9-1 and CmHSP17.9-2 genes was highest in the terminal buds of the chrysanthemum, followed by the leaves. CmHSP17.9-1 and CmHSP17.9-2 overex-pression vectors were constructed and used to transform the chrysanthemum; overexpression of these genes led to the chrysanthemum phenotypes being less affected by high-temperature, and the antioxidant capacity was enhanced. The results showed that chrysanthemum with overex-pression of the CmHSP17.9-1 and CmHSP17.9-2 genes had stronger tolerance than the wild type chrysanthemum after high-temperature treatment or some degree of heat exercise, and overex-pression of the CmHSP17.9-1 gene led to stronger heat resistance than that of the CmHSP17.9-2 gene, providing an important theoretical basis for the subsequent molecular breeding and pro-duction applications of chrysanthemum.

Causal association between cardiovascular proteins and membranous nephropathy: a bidirectional Mendelian randomization.

PURPOSE: Multiple circulating proteins have been reported to participate in human diseases. However, the association between cardiovascular proteins and membranous nephropathy (MN) remained profoundly elusive. METHODS: A bidirectional Mendelian randomization (MR) analysis was conducted to explore the causal correlation between ninety cardiovascular proteins and MN. Genome-wide association study (GWAS) data of cardiovascular proteins and MN were all from European research. Inverse variance weighted (IVW) was used as the main approach. Moreover, MR-Egger, weighted median, weighted mode, and simple mode were also performed. Cochrane's Q test, MR-Egger, and MR-PRESSO were conducted for sensitivity analysis. RESULTS: According to IVW method, fatty acid-binding protein and thrombomodulin (TM) were identified as risk factors for MN, while a protective role was detected in tissue-type plasminogen activator. Additionally, MN was associated with an elevated level of macrophage colony-stimulating factor 1, stem cell factor, TM, and tissue factor. Reversely, MN was also correlated with a downregulated level of beta-nerve growth factor, Cathepsin D, hepatocyte growth factor, interleukin-6 receptor subunit alpha, macrophage colony-stimulating factor 1, and myeloperoxidase. In the sensitivity analysis, no significant pleiotropy and heterogeneity was detected. CONCLUSION: This was the first study to reveal the causal association between cardiovascular proteins and MN. These specific cardiovascular proteins could be novel biomarkers for MN, and is helpful for timely identify the risk of other diseases that might result from MN. However, further clinical studies are needed to confirm our results.

Exploring the chemical components of Kuanchang-Shu granule and its protective effects of postoperative ileus in rats by regulating AKT/HSP90AA1/eNOS pathway.

BACKGROUND: Postoperative ileus (POI) is a common obstruction of intestinal content passage caused by almost all abdominal operations that seriously strokes the quality of life of patients. Kuanchang-Shu granule (KCSG), a classic modified prescription based on "Da-Cheng-Qi Decoction", has obtained satisfactory efficacy in the clinical therapeutics of POI. However, its material basis and holistic molecular mechanism against POI have not been revealed. METHODS: The chemical ingredients of KCSG were first characterized by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Subsequently, an integration strategy of the network pharmacology and molecular docking based on above identified ingredients was performed to unveil the potential targets involved in the treatment of KCSG on POI. Finally, intestinal manipulation induced rat POI model was constructed to verify the efficacy and predicted mechanism of KCSG against POI. RESULTS: In total, 246 ingredients mainly including organic acids, flavonoids, quinones, alkaloids, terpenoids, phenylpropanoids and phenols were identified. 41 essential ingredients, 24 crucial targets as well as 15 relevant signaling pathways were acquired based on network pharmacology analysis. Pharmacodynamic research showed that KCSG treatment could protect intestinal histological damage, promote the recovery of measurement of gastrointestinal transit disorder and inhibit the secretion of myeloperoxidase in the distal ileum tissues. The up-regulated expression of p-AKT and down-regulated expression of p-eNOS and HSP9OAA1 predicted by molecular docking and validated by western blotting showed that AKT/eNOS/HSP90AA1 pathway may be one of the crucial mechanisms that mediates the protective effect of KCSG.

The causal association of specific gut microbiota on the risk of membranous nephropathy: a Mendelian randomization study.

PURPOSE: Gut microbiota transplantation has been reported to improve the renal function of membranous nephropathy (MN). However, whether there is a causal effect of gut microbiota on MN remained unclear. METHODS: We performed two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the main approach to evaluate the causal relationship between gut microbiota and MN. Additional methods including MR-Egger regression, weighted median, and MR-weighted mode were also conducted. Cochrane's Q test, MR-Egger regression, and MR-PRESSO were employed to detect heterogeneity and pleiotropy, respectively. RESULTS: A total of 196 gut microbiota were examined. After IVW and sensitivity analysis, eight gut bacteria taxa were observed causal effects on the risk of MN. Specifically, Genus. Oscillibacter was a protective factor (OR: 0.57; 95% CI 0.328-0.979; P = 0.042), while Class. Melainabacteria (OR: 1.51; 95% CI 1.004-2.277; P = 0.048), Genus. Butyricicoccus (OR: 2.16; 95% CI 1.005-4.621; P = 0.048), Genus. Catenibacterium (OR: 1.49; 95% CI 1.043-2.134; P = 0.028), Genus.Ruminiclostridium5 (OR: 1.74; 95% CI 1.053-2.862; P = 0.030), Genus. Ruminococcaceae UCG-003 (OR: 1.73; 95% CI 1.110-2.692; P = 0.015), Order. Bacillales (OR: 1.52; 95% CI 1.135-2.025; P = 0.0048) and Order. Gastranaerophilales (OR: 1.45; 95% CI 1.010-2.085; P = 0.044) were risk factors. Heterogeneity was not significant for most single-nucleotide polymorphisms, and no statistical difference in pleiotropy. CONCLUSIONS: This study first indicated the causal association between specific gut microbiota and MN, which would be of great significance to guide clinical prevention and treatment in MN.

Transcriptome analysis during axillary bud growth in chrysanthemum (chrysanthemum×morifolium).

The chrysanthemum DgLsL gene, homologous with tomato Ls, is one of the earliest expressed genes controlling axillary meristem initiation. In this study, the wild-type chrysanthemum (CW) and DgLsL-overexpressed line 15 (C15) were used to investigate the regulatory mechanism of axillary bud development in chrysanthemum. Transcriptome sequencing was carried out to detect the differentially expressed genes of the axillary buds 0 h, 24 h and 48 h after decapitation. The phenotypic results showed that the number of axillary buds of C15 was significantly higher than CW. A total of 9,224 DEGs were identified in C15-0 vs. CW-0, 10,622 DEGs in C15-24 vs. CW-24, and 8,929 DEGs in C15-48 vs. CW-48.GO and KEGG pathway enrichment analyses showed that the genes of the flavonoid, phenylpropanoids and plant hormone pathways appeared to be differentially expressed, indicating their important roles in axillary bud germination. DgLsL reduces GA content in axillary buds by promoting GA2ox expression.These results confirmed previous studies on axillary bud germination and growth, and revealed the important roles of genes involved in plant hormone biosynthesis and signal transduction, aiding in the study of the gene patterns involved in axillary bud germination and growth.

Combination of rituximab and short-term glucocorticoids in the treatment of anti-phospholipase A2 receptor antibody positive idiopathic membranous nephropathy.

Rituximab (RTX) has been the first option in idiopathic membranous nephropathy (IMN). However, the clinical effect was not very satisfactory. This study aimed to explore the clinical efficacy and safety of the combination of RTX and glucocorticoids (GC) in anti-phospholipase A2 receptor (anti-PLA2R) antibody positive IMN. Sixty-six patients were randomly divided into RTX/GC group (RTX infusion plus short-term oral GC) and RTX group (RTX infusion alone) in this prospective cohort study. Complete remission (CR) and partial remission (PR) were the primary outcomes. Adverse events were the secondary outcomes. The laboratory index including serum albumin, 24 h urinary protein, serum creatinine, estimated glomerular filtration rate, and anti-PLA2R antibody titer were also monitored. All patients were followed for at least 12 months. During the 12-month follow-up, the composite remission rates in RTX/GC and RTX groups were 74.3% and 67.7%, and the CR rates were 34.3% and 19.4%, respectively. The median time of remission in RTX/GC group was shorter than the RTX group (P < 0.001). Compared with RTX monotherapy, the combination of RTX and GC significantly decreased the anti-PLA2R antibody titer (P = 0.028). No significant difference was observed in the incidence of adverse events. The results of the Kaplan-Meier survival analysis indicated that the cumulative CR rate and cumulative composite remission rate in RTX/GC group were all better than the RTX group (P = 0.043, P = 0.040, respectively). The combination of RTX and GC was better than RTX monotherapy without increasing the adverse events in the treatment of IMN.

New-onset and relapsed thrombotic microangiopathy post-COVID-19 vaccination.

Thrombotic microangiopathy (TMA) associated with coronavirus disease 2019 (COVID-19) vaccination has been reported, however, the clinical characteristics and pathogenesis remained mysterious. We reviewed 84 TMA cases post-COVID-19 vaccination, including 64 patients diagnosed with thrombotic thrombocytopenic purpura (TTP), 17 cases presented as atypical hemolytic uremic syndrome (aHUS), and three cases manifested as unclassified TMA. TMA episodes were mostly associated with messenger RNA vaccines. For TTP, 67.6% of females developed symptoms after the first dose of the vaccine, and 63.0% of males were secondary to the second dose (p = 0.015). Compared with TTP, aHUS generally appeared within 7 days (p = 0.002) and showed higher levels of serum creatinine (p < 0.001). 87.5% of TTP received plasma exchange (PEX)-based treatment, and 52.9% of aHUS adopted non-PEX-based therapies (p < 0.001). Mechanistically, complement dysfunction, neutrophil activation, and the generation of pathogenic autoantibodies resulting from molecular mimicry contribute to explaining the pathogenesis of TMA post-COVID-19 vaccination.

Inverse association between caffeine intake and albuminuria in US adults: an analysis of NHANES 2005-2016.

OBJECTIVES: Albuminuria is a significant biomarker of various kidney diseases and is associated with renal outcome. Recently, caffeine intake has shown potential renoprotective effects. However, the relationship between caffeine intake and albuminuria remains profoundly elusive. METHODS: We conducted a cross-sectional study aimed to explore the association between caffeine intake and albuminuria in the American adult population using the data acquired from the National Health and Nutrition Examination Survey (NHANES) 2005-2016. Caffeine intake was assessed by 24-h dietary recalls, and albuminuria was assessed by albumin-to-creatinine ratio. Multivariate logistic regression was performed to explore the independent association between caffeine intake and albuminuria. Subgroup analysis and interaction tests were also conducted. RESULTS: Among 23,060 participants, 11.8% of the individuals exhibited albuminuria, and the prevalence of albuminuria decreased with higher caffeine intake tertiles (Tertile 1: 13%; Tertile 2: 11.9%; Tertile 3: 10.5%; P < 0.001). After adjusted potential confounders, the results of logistic regression indicated that a higher caffeine intake was associated with a decreased risk of albuminuria (OR = 0.903; 95% CI: 0.84, 0.97; P = 0.007), especially in females and the participants aged <60 years and chronic kidney disease stage II. CONCLUSION: The present study first indicated an inverse correlation between caffeine intake and albuminuria, which further confirmed the potentially protective effects of caffeine on the kidney.

Cognitive and motor cortex activation during robot-assisted multi-sensory interactive motor rehabilitation training: An fNIRS based pilot study.

Objective: This study aimed to evaluate the effects of multiple virtual reality (VR) interaction modalities based on force-haptic feedback combined with visual or auditory feedback in different ways on cerebral cortical activation by functional near-infrared spectroscopy (fNIRS). Methods: A modular multi-sensory VR interaction system based on a planar upper-limb rehabilitation robot was developed. Twenty healthy participants completed active elbow flexion and extension training in four VR interaction patterns, including haptic (H), haptic + auditory (HA), haptic + visual (HV), and haptic + visual + auditory (HVA). Cortical activation changes in the sensorimotor cortex (SMC), premotor cortex (PMC), and prefrontal cortex (PFC) were measured. Results: Four interaction patterns all had significant activation effects on the motor and cognitive regions of the cerebral cortex (p < 0.05). Among them, in the HVA interaction mode, the cortical activation of each ROI was the strongest, followed by HV, HA, and H. The connectivity between channels of SMC and bilateral PFC, as well as the connectivity between channels in PMC, was the strongest under HVA and HV conditions. Besides, the two-way ANOVA of visual and auditory feedback showed that it was difficult for auditory feedback to have a strong impact on activation without visual feedback. In addition, under the condition of visual feedback, the effect of fusion auditory feedback on the activation degree was significantly higher than that of no auditory feedback. Conclusions: The interaction mode of visual, auditory, and haptic multi-sensory integration is conducive to stronger cortical activation and cognitive control. Besides, there is an interaction effect between visual and auditory feedback, thus improving the cortical activation level. This research enriches the research on activation and connectivity of cognitive and motor cortex in the process of modular multi-sensory interaction training of rehabilitation robots. These conclusions provide a theoretical basis for the optimal design of the interaction mode of the rehabilitation robot and the possible scheme of clinical VR rehabilitation.

Cortical activation in robot-assisted dynamic and static resistance training combining VR interaction: An fNIRS based pilot study.

BACKGROUND: There are few isometric training systems based on upper limb rehabilitation robots. Its efficacy and neural mechanism are not well understood. OBJECTIVE: This study aims to investigate the cortex activation of dynamic resistance and static (isometric) training based on upper limb rehabilitation robot combined with virtual reality (VR) interaction by using functional near-infrared spectroscopy (fNIRS). METHODS: Twenty subjects were included in this study. The experiment adopts the block paradigm design. Experiment in dynamic and static conditions consisted of three trials, each consisting of task (60 s)-rest (40 s). The neural activities of the sensorimotor cortex (SMC), premotor cortex (PMC) and prefrontal cortex (PFC) were measured. The cortex activation and functional connectivity (FC) were analyzed. RESULTS: Both the dynamic and static training can activate SMC, PMC, and PFC. In SMC and PMC, the activation of static training was stronger than dynamic training, there were significant differences between the two modes of each region of interest (ROI) (p < 0.05) (SMC: p = 0.022, ES = 0.72, PMC: p = 0.039, ES = 0.63). Besides, the FC between all ROIs of the static training was stronger than that of the dynamic training. CONCLUSION: The static training based on upper limb rehabilitation robot may better facilitate the cortical activation associated with motor control.

New-Onset and Relapsed Membranous Nephropathy post SARS-CoV-2 and COVID-19 Vaccination.

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak and COVID-19 vaccination, new-onset and relapsed clinical cases of membranous nephropathy (MN) have been reported. However, their clinical characteristics and pathogenesis remained unclear. In this article, we collected five cases of MN associated with SARS-CoV-2 infection and 37 related to COVID-19 vaccination. Of these five cases, four (4/5, 80%) had acute kidney injury (AKI) at disease onset. Phospholipase A2 receptor (PLA2R) in kidney tissue was negative in three (3/5, 60%) patients, and no deposition of virus particles was measured among all patients. Conventional immunosuppressive drugs could induce disease remission. The underlying pathogenesis included the subepithelial deposition of viral antigens and aberrant immune response. New-onset and relapsed MN after COVID-19 vaccination generally occurred within two weeks after the second dose of vaccine. Almost 27% of patients (10/37) suffered from AKI. In total, 11 of 14 cases showed positive for PLA2R, and 20 of 26 (76.9%) presented with an elevated serum phospholipase A2 receptor antibody (PLA2R-Ab), in which 8 cases exceeded 50 RU/mL. Conventional immunosuppressive medications combined with rituximab were found more beneficial to disease remission for relapsed patients. In contrast, new-onset patients responded to conservative treatment. Overall, most patients (24/37, 64.9%) had a favorable prognosis. Cross immunity and enhanced immune response might contribute to explaining the mechanisms of MN post COVID-19 vaccination.

LncRNA ANRIL mediates endothelial dysfunction through BDNF downregulation in chronic kidney disease.

Endothelial dysfunction is common in patients with chronic kidney disease (CKD), but the mechanism is unknown. In this study, we found that the circulating ANRIL level was increased and correlated with vascular endothelial dysfunction in patients with CKD, also negatively correlated with plasma brain-derived neurotrophic factor (BDNF) concentration. We constructed the ANRIL knockout mice model, and found that ANRIL deficiency reversed the abnormal expression of BDNF, along with endothelial nitric oxide synthase (eNOS), vascular adhesion molecule 1 (VCAM-1) and Von Willebrand factor (vWF). Meanwhile, mitochondrial dynamics-related proteins, Dynamin-related protein 1 (Drp1) and mitofusins (Mfn2) level were also recovered. In addition, in vitro, serum derived from CKD patients and uremia toxins induced abnormal expression of ANRIL. By making use of the gain- and loss-of-function approaches, we observed that ANRIL mediated endothelial dysfunction through BDNF downregulation. To explore the specific mechanism, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) were used to explore the binding of ANRIL to histone methyltransferase Enhancer of zeste homolog 2 (EZH2). Further experiments found increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) levels at the BDNF promoter region. Collectively, we demonstrated that ANRIL mediate BDNF transcriptional suppression through recruitment of EZH2 to the BDNF promoter region, then regulated the proteins expression related to endothelial function and mitochondrial dynamics. This study provides new insights for the study of endothelial dysfunction in CKD.

Chronic Kidney Disease and Cancer: Inter-Relationships and Mechanisms.

Chronic kidney disease (CKD) has been recognized as an increasingly serious public health problem globally over the decades. Accumulating evidence has shown that the incidence rate of cancer was relatively higher in CKD patients than that in general population, which, mechanistically, may be related to chronic inflammation, accumulation of carcinogenic compounds, oxidative stress, impairment of DNA repair, excessive parathyroid hormone and changes in intestinal microbiota, etc. And in patients with cancer, regardless of tumor types or anticancer treatment, it has been indicated that the morbidity and incidence rate of concomitant CKD was also increased, suggesting a complex inter-relationship between CKD and cancer and arousing increasing attention from both nephrologists and oncologists. This narrative review focused on the correlation between CKD and cancer, and underlying molecular mechanisms, which might provide an overview of novel interdisciplinary research interests and the potential challenges related to the screening and treatment of CKD and cancer. A better understanding of this field might be of help for both nephrologists and oncologists in the clinical practice.

Cloning and Functional Verification of CmRAX2 Gene Associated with Chrysanthemum Lateral Branches Development.

Chrysanthemum (Chrysanthemum morifolium), as one of the four major cut flowers in the world, occupies a large position in the world's fresh cut flower market. The RAX2 gene is an R2R3 MYB transcription factor that is associated with the development of the axillary bud. In this study, the CmRAX2 gene cloned by homologous cloning in Chrysanthemum morifolium 'Jinba' is localized in the nucleus and cytoplasm, having a complete open reading frame (ORF) of 1050 bp and encoding 350 amino acids. The transactivation assay in yeast indicates that CmRAX2 is a transcriptional activator. Quantitative Real-Time PCR (qRT-PCR) Analysis indicated that CmRAX2 was preferentially expressed in the lateral branches and roots of Chrysanthemum morifolium 'Jinba', 14.11 and 10.69 times more than in leaves. After the overexpression vector of CmRAX2 was constructed and transformed into Chrysanthemum morifolium 'Jinba', it was found that the number of lateral branches and plant height increased, and the emergence time of lateral branches and rooting time advanced after the overexpression of CmRAX2. The results showed that CmRAX2 can promote the lateral bud development of the chrysanthemum, which provides an important theoretical basis for the subsequent molecular breeding and standardized production of the chrysanthemum.

Long Non-Coding RNAs in the Pathogenesis of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus, with relatively high morbidity and mortality globally but still in short therapeutic options. Over the decades, a large body of data has demonstrated that oxidative stress, inflammatory responses, and hemodynamic disorders might exert critical influence in the initiation and development of DKD, whereas the delicate pathogenesis of DKD remains profoundly elusive. Recently, long non-coding RNAs (lncRNAs), extensively studied in the field of cancer, are attracting increasing attentions on the development of diabetes mellitus and its complications including DKD, diabetic retinopathy, and diabetic cardiomyopathy. In this review, we chiefly focused on abnormal expression and function of lncRNAs in major resident cells (mesangial cell, endothelial cell, podocyte, and tubular epithelial cell) in the kidney, summarized the critical roles of lncRNAs in the pathogenesis of DKD, and elaborated their potential therapeutic significance, in order to advance our knowledge in this field, which might help in future research and clinical treatment for the disease.

Long Noncoding RNA ENSG00000254693 Promotes Diabetic Kidney Disease via Interacting with HuR.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes mellitus (DM), without suitable therapies, causing end-stage renal diseases (ESRDs) ultimately. Moreover, there is increasing evidence demonstrating that long noncoding RNAs (lncRNAs) play crucial roles in the development of DKD. Our RNA sequencing data revealed a large group of differentially expressed lncRNAs in renal tissues of DKD, of which lncRNA ENSG00000254693 (lncRNA 254693 for short) changed drastically. In this study, we found that the expression of lncRNA 254693 was increased in both DKD patients and high-glucose-induced human podocytes. 5'/3'RACE and Northern blot assays were used to find the full length of lncRNA ENSG00000254693 which is 558 nucleotides and nonisoform that existed in human podocyte. Downregulation of lncRNA 254693 remarkably reversed the elevation of inflammation, apoptosis, and podocyte injury caused by high glucose. Then, we did bioinformatics analysis via RBPDB and found that lncRNA 254693 can combine with HuR, a RNA binding protein. Meanwhile, immunofluorescence and in situ hybridization double staining was used to prove the existence of colocalization between them. Intriguingly, lncRNA 254693 knockdown decreased HuR levels, while HuR knockdown also decreased the level of lncRNA 254693 and its stability. After this, RNA immunoprecipitation assay results confirmed the binding association between them again. In addition, we found that HuR was increased in high glucose-induced podocytes, and the silence of HuR could alleviate podocyte injury, inflammation, and apoptosis. These results together suggested a novel feedback regulation between lncRNA 254693 and HuR which could involve in podocyte injury and may serve as a predicted target for DKD therapies.

Role of SIK1 in the transition of acute kidney injury into chronic kidney disease.

BACKGROUND: Acute kidney injury (AKI), with a high morbidity and mortality, is recognized as a risk factor for chronic kidney disease (CKD). AKI-CKD transition has been regarded as one of the most pressing unmet needs in renal diseases. Recently, studies have showed that salt inducible kinase 1 (SIK1) plays a role in epithelial-mesenchymal transition (EMT) and inflammation, which are the hallmarks of AKI-CKD transition. However, whether SIK1 is involved in AKI-CKD transition and by what mechanism it regulates AKI-CKD transition remains unknown. METHODS: We firstly detected the expression of SIK1 in kidney tissues of AKI patients and AKI mice by immunohistochemistry staining, and then we established Aristolochic acid (AA)-induced AKI-CKD transition model in C57BL/6 mice and HK2 cells. Subsequently, we performed immunohistochemistry staining, ELISA, real-time PCR, Western blot, immunofluorescence staining and Transwell assay to explore the role and underlying mechanism of SIK1 on AKI-CKD transition. RESULTS: The expression of SIK1 was down-regulated in AKI patients, AKI mice, AA-induced AKI-CKD transition mice, and HK2 cells. Functional analysis revealed that overexpression of SIK1 alleviated AA-induced AKI-CKD transition and HK2 cells injury in vivo and in vitro. Mechanistically, we demonstrated that SIK1 mediated AA-induced AKI-CKD transition by regulating WNT/ß-catenin signaling, the canonical pathway involved in EMT, inflammation and renal fibrosis. In addition, we discovered that inhibition of WNT/ß-catenin pathway and its downstream transcription factor Twist1 ameliorated HK2 cells injury, delaying the progression of AKI-CKD transition. CONCLUSIONS: Our study demonstrated, for the first time, a protective role of SIK1 in AKI-CKD transition by regulating WNT/ß-catenin signaling pathway and its downstream transcription factor Twist1, which will provide novel insights into the prevention and treatment AKI-CKD transition in the future.

Podocyte-derived extracellular vesicles mediate renal proximal tubule cells dedifferentiation via microRNA-221 in diabetic nephropathy.

Podocyte injury is a key event in the initiation of Diabetic nephropathy (DN). Tubulointerstitium, especially the proximal tubule has been regarded as a target of injury. In the present study, we showed that podocytes induced dedifferentiation of proximal tubular epithelial cells(PTECs) in high-glucose conditions and extracellular vesicles (EVs) mediates the interaction. Then we extracted and identified these EVs derived from podocytes as exosome, further, the EVs induced PTECs dedifferentiation. Total microRNA(miRNA) expression of podocyte-derived EVs was extracted and miR-221 expression was remarkably increased. By making use of the miRNA gain- and loss-of-function approaches, we observed that miR-221 mediated PTECs dedifferentiation. In addition, a dual-luciferase reporter assay confirmed that miR-221 direct target DKK2, which was an inhibitor of Wnt signaling, and overexpression of miR-221 significantly resulted in ß-catenin nuclear accumulation. Moreover, we regulated the expression of ß-catenin and demonstrated that miR-221 in EVs mediated proximal tubule cells injury through Wnt/ß-catenin signaling. Furthermore, inhibition of miR-221 in diabetic mice reversed the abnormal expression of PTECs dedifferentiation related protein. These findings provide unique insights in the mechanisms of proximal tubule cell injury in diabetic nephropathy.

Leptin promotes endothelial dysfunction in chronic kidney disease by modulating the MTA1-mediated WNT/ß-catenin pathway.

Endothelial dysfunction (ED) has a high incidence in chronic kidney disease (CKD) and is identified as a precursor to cardiovascular events. Recent studies suggest that leptin may be the missing link between ED and CKD. The objective of this study was to investigate the mechanism by which leptin causes ED and the connection with leptin and indicators of ED in CKD patients. Analysis of leptin-treated human umbilical vein endothelial cells (HUVECs) showed increased expression of interleukin 6 (IL-6), endothelin 1 (ET-1) and human monocyte chemoattractant protein 1 (MCP-1), resulting in F-actin recombination and vinculin aggregation as well as endothelial cell migration. In vitro studies have shown that leptin leads to increased WNT1 expression and the accumulation of ß-catenin. Metastasis-associated protein 1 (MTA1), a critical upstream modifier of WNT1 signaling, increased the expression level in leptin-mediated regulation. In contrast, opposite results were observed when cells are transfected with MTA1 or WNT1 shRNA lentivirus vectors. Among 160 patients with CKD and 160 healthy subjects, patients with CKD had significantly higher serum leptin levels than those of the control group, which were positively correlated with increased levels of IL-6, ET-1 and MCP-1. However, these levels were negatively correlated with flow-mediated dilatation (FMD). Hence, these investigations provided novel information on the increased serum leptin levels in CKD patients leading to ED via the MTA1-WNT/ß-catenin pathway.