Single-cell transcriptomics reveals the ameliorative effect of rosmarinic acid on diabetic nephropathy-induced kidney injury by modulating oxidative stress and inflammation.

Diabetic nephropathy (DN) is a severe complication of diabetes, characterized by changes in kidney structure and function. The natural product rosmarinic acid (RA) has demonstrated therapeutic effects, including anti-inflammation and anti-oxidative-stress, in renal damage or dysfunction. In this study, we characterized the heterogeneity of the cellular response in kidneys to DN-induced injury and RA treatment at single cell levels. Our results demonstrated that RA significantly alleviated renal tubular epithelial injury, particularly in the proximal tubular S1 segment and on glomerular epithelial cells known as podocytes, while attenuating the inflammatory response of macrophages, oxidative stress, and cytotoxicity of natural killer cells. These findings provide a comprehensive understanding of the mechanisms by which RA alleviates kidney damage, oxidative stress, and inflammation, offering valuable guidance for the clinical application of RA in the treatment of DN.

Delayed intestinal perforation associated with peritoneal dialysis: A case report of maintaining dialysis after perforation.

Delayed intestinal perforation has various manifestations. For peritonitis with delayed treatment and multi-bacterial peritonitis, we should be alert to the occurrence of this rare complication. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis. Delayed intestinal perforation of peritoneal dialysis catheter is a rare but serious complication. We reported a 49-year-old patient who had been hospitalized twice within 3 months due to poor drainage of the peritoneal dialysis catheter. During the first hospitalization, peritoneal dialysis-related peritonitis was diagnosed, and a variety of bacterial infections were cultivated. However, at that time, the actual peritoneal dialysis catheter-related intestinal perforation was missed, and he was discharged after anti-infection treatment until a clinical cure was met. After more than 2 months of normal peritoneal dialysis after returning home, the patient again had poor drainage of the peritoneal dialysis catheter, accompanied by the outflow of yellowish-brown sediment. It was found that the peritoneal dialysis catheter had evidence of intestinal perforation. After the removal of the catheter and intestinal repair, he recovered and was discharged from the hospital and received long-term hemodialysis treatment. In the case of delayed intestinal perforation, peritoneal dialysis was maintained normally for more than 2 months, which was an unprecedented situation in previous case reports. In addition, we should be alert to the occurrence of this rare complication, especially when we find the occurrence of polybacterial Peritonitis. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis.

Integrated proteome and malonylome analyses reveal the potential meaning of TLN1 and ACTB in end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a condition that is characterized by the loss of kidney function. ESRD patients suffer from various endothelial dysfunctions, inflammation, and immune system defects. Lysine malonylation (Kmal) is a recently discovered post-translational modification (PTM). Although Kmal has the ability to regulate a wide range of biological processes in various organisms, its specific role in ESRD is limited. METHODS: In this study, the affinity enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have been used to create the first global proteome and malonyl proteome (malonylome) profiles of peripheral blood mononuclear cells (PBMCs) from twenty patients with ESRD and eighty-one controls. RESULTS: On analysis, 793 differentially expressed proteins (DEPs) and 12 differentially malonylated proteins (DMPs) with 16 Kmal sites were identified. The Rap1 signaling pathway and platelet activation pathway were found to be important in the development of chronic kidney disease (CKD), as were DMPs TLN1 and ACTB, as well as one malonylated site. One conserved Kmal motif was also discovered. CONCLUSIONS: These findings provided the first report on the Kmal profile in ESRD, which could be useful in understanding the potential role of lysine malonylation modification in the development of ESRD.

Downregulation of ARNTL in renal tubules of diabetic db/db mice reduces kidney injury by inhibiting ferroptosis.

BACKGROUND: The prevalence of ferroptosis in diabetic kidney tubules has been documented, yet the underlying mechanism remains elusive. The aim of this study was to ascertain the pivotal gene linked to ferroptosis and establish a novel target for the prevention and management of diabetic kidney disease (DKD). METHODS: Transcriptomics data (GSE184836) from DKD mice (C57BLKS/J) were retrieved from the GEO database and intersected with ferroptosis-related genes from FerrDb. Then, differentially expressed genes associated with ferroptosis in the glomeruli and tubules were screened. Gene ontology analysis and protein-protein interaction network construction were used to identify key genes. Western blotting and real-time quantitative polymerase chain reaction were employed to validate the expression in the same model. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) expression in patients and mice with DKD was assessed using immunohistochemistry staining. ARNTL knockdown in C57BLKS/J mice was established and plasma malonaldehyde, superoxide dismutase, and renal pathology were analyzed. The efficacy of ARNTL knockdown was evaluated using proteomics analysis. Mitochondrial morphology was observed using transmission electron microscopy. RESULTS: ARNTL was screened by bioinformatics analysis and its overexpression verified in patients and mice with DKD. ARNTL knockdown reduced oxidative stress in plasma. Kidney proteomics revealed that ferroptosis was inhibited. The reduction of the classic alteration in mitochondrial morphology associated with ferroptosis was also observed. Gene set enrichment analysis demonstrated that the downregulation of the TGFß pathway coincided with a decrease in collagen protein and TGFß1 levels. CONCLUSIONS: The ferroptosis-associated gene ARNTL is a potential target for treating DKD.

New insights into the mechanisms of diabetic kidney disease: Role of circadian rhythm and Bmal1.

It is common for diabetic kidney disease (DKD) to be complicated by abnormal blood glucose, blood lipids, and blood pressure rhythms. Thus, it is essential to examine diagnostic and treatment plans from the perspective of circadian disruption. This brief review discusses the clinical relevance of circadian rhythms in DKD and how the core clock gene encoding brain and muscle arnt-like protein 1 (BMAL1) functions owing to the importance of circadian rhythm disruption processes, including the excretion of urinary protein and irregular blood pressure, which occur in DKD. Exploring Bmal1 and its potential mechanisms and signaling pathways in DKD following contact with Sirt1 and NF-κB is novel and important. Finally, potential pharmacological and behavioral intervention strategies for DKD circadian rhythm disturbance are outlined. This review aids in unveiling novel, potential molecular targets for DKD based on circadian rhythms.

Hyperkalaemia prevalence and dialysis patterns in Chinese patients on haemodialysis: an interim analysis of a prospective cohort study (PRECEDE-K).

BACKGROUND: Hyperkalaemia is a known risk factor for cardiac arrhythmia and mortality in patients on haemodialysis. Despite standard adequate haemodialysis, hyperkalaemia is common in patients with end-stage renal disease (ESRD) at interdialytic intervals. Data on hyperkalaemia burden and its effects on dialysis patterns and serum potassium (sK) fluctuations in patients on haemodialysis in China remain limited. The prospective, observational cohort study (PRECEDE-K; NCT04799067) investigated the prevalence, recurrence, and treatment patterns of hyperkalaemia in Chinese patients with ESRD on haemodialysis. METHODS: Six hundred adult patients were consecutively enrolled from 15 secondary and tertiary hospitals in China. In this interim analysis, we report the baseline characteristics of the cohort, the prevalence of predialysis hyperkalaemia (sK > 5.0 mmol/L), and the trends in serum-dialysate potassium gradient and intradialytic sK shift at Visit 1 (following a long interdialytic interval [LIDI]). RESULTS: At baseline, most patients (85.6%) received three-times weekly dialysis; mean duration was 4.0 h. Mean urea reduction ratio was 68.0% and Kt/V was 1.45; 60.0% of patients had prior hyperkalaemia (previous 6 months). At Visit 1, mean predialysis sK was 4.83 mmol/L, and 39.6% of patients had hyperkalaemia. Most patients (97.7%) received a dialysate potassium concentration of 2.0 mmol/L. The serum-dialysate potassium gradient was greater than 3 mmol/L for over 40% of the cohort (1- < 2, 2- < 3, 3- < 4, and ≥ 4 mmol/L in 13.6%, 45.1%, 35.7%, and 5.2% of patients, respectively; mean: 2.8 mmol/L). The intradialytic sK reduction was 1- < 3 mmol/L for most patients (0- < 1, 1- < 2, 2- < 3, and ≥ 3 mmol/L in 24.2%, 62.2%, 12.8%, and 0.9% of patients, respectively; mean: 1.4 mmol/L). CONCLUSIONS: Hyperkalaemia after a LIDI was common in this real-world cohort of Chinese patients despite standard adequate haemodialysis, and led to large serum-dialysate potassium gradients and intradialytic sK shifts. Previous studies have shown hyperkalaemia and sK fluctuations are highly correlated with poor prognosis. Effective potassium-lowering treatments should be evaluated for the improvement of long-term prognosis through the control of hyperkalaemia and sK fluctuations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04799067.

Urinary microbiota and serum metabolite analysis in patients with diabetic kidney disease.

Background: Diabetic kidney disease (DKD) is a common and potentially fatal consequence of diabetes. Chronic renal failure or end-stage renal disease may result over time. Numerous studies have demonstrated the function of the microbiota in health and disease. The use of advanced urine culture techniques revealed the presence of resident microbiota in the urinary tract, undermining the idea of urine sterility. Studies have demonstrated that the urine microbiota is related with urological illnesses; nevertheless, the fundamental mechanisms by which the urinary microbiota influences the incidence and progression of DKD remain unclear. The purpose of this research was to describe key characteristics of the patients with DKD urinary microbiota in order to facilitate the development of diagnostic and therapeutic for DKD. Methods: We evaluated the structure and composition of the microbiota extracted from urine samples taken from DKD patients (n = 19) and matched healthy controls (n = 15) using 16S rRNA gene sequencing. Meanwhile, serum metabolite profiles were compared using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Associations between clinical characteristics, urine microbiota, and serum metabolites were also examined. Finally, the interaction between urine microbiota and serum metabolites was clarified based on differential metabolite abundance analysis. Results: The findings indicated that the DKD had a distinct urinary microbiota from the healthy controls (HC). Taxonomic investigations indicated that the DKD microbiome had less alpha diversity than a control group. Proteobacteria and Acidobacteria phyla increased in the DKD, while Firmicutes and Bacteroidetes decreased significantly (P < 0.05). Acidobacteria was the most prevalent microbiota in the DKD, as determined by the Linear discriminant analysis Effect Size (LEfSe) plot. Changes in the urinary microbiota of DKD also had an effect on the makeup of metabolites. Short-chain fatty acids (SCFAs) and protein-bound uremic toxins (PBUTs) were shown to be specific. Then we discovered that arginine and proline metabolism was the primary mechanism involved in the regulation of diabetic kidney disease. Conclusions: This study placed the urinary microbiota and serum metabolite of DKD patients into a functional framework and identified the most abundant microbiota in DKD (Proteobacteria and Acidobacteria). Arginine metabolites may have a major effect on DKD patients, which correlated with the progression of DKD.

Machine learning-based intradialytic hypotension prediction of patients undergoing hemodialysis: A multicenter retrospective study.

BACKGROUND AND OBJECTIVE: Intradialytic hypotension (IDH) is closely associated with adverse clinical outcomes in HD-patients. An IDH predictor model is important for IDH risk screening and clinical decision-making. In this study, we used Machine learning (ML) to develop IDH model for risk prediction in HD patients. METHODS: 62,227 dialysis sessions were randomly partitioned into training data (70%), test data (20%), and validation data (10%). IDH-A model based on twenty-seven variables was constructed for risk prediction for the next HD treatment. IDH-B model based on ten variables from 64,870 dialysis sessions was developed for risk assessment before each HD treatment. Light Gradient Boosting Machine (LightGBM), Linear Discriminant Analysis, support vector machines, XGBoost, TabNet, and multilayer perceptron were used to develop the predictor model. RESULTS: In IDH-A model, we identified the LightGBM method as the best-performing and interpretable model with C- statistics of 0.82 in Fall30Nadir90 definitions, which was higher than those obtained using the other models (P<0.01). In other IDH standards of Nadir90, Nadir100, Fall20, Fall30, and Fall20Nadir90, the LightGBM method had a performance with C- statistics ranged 0.77 to 0.89. As a complementary application, the LightGBM model in IDH-B model achieved C- statistics of 0.68 in Fall30Nadir90 definitions and 0.69 to 0.78 in the other five IDH standards, which were also higher than the other methods, respectively. CONCLUSION: Use ML, we identified the LightGBM method as the good-performing and interpretable model. We identified the top variables as the high-risk factors for IDH incident in HD-patient. IDH-A and IDH-B model can usefully complement each other for risk prediction and further facilitate timely intervention through applied into different clinical setting.

Spatial proteomics landscape and immune signature analysis of renal sample of lupus nephritis based on laser-captured microsection.

OBJECTIVE: We aimed to reveal a spatial proteomic and immune signature of kidney function regions in lupus nephritis (LN). MATERIAL AND METHODS: The laser capture microdissection (LCM) was used to isolate the glomerulus, tubules, and interstitial of the kidney from paraffin samples. The data-independent acquisition (DIA) method was used to collect proteomics data. The bioinformatic analysis was performed. RESULTS: A total of 49,658 peptides and 4056 proteins were quantitated. Our results first showed that a high proportion of activated NK cells, naive B cells, and neutrophils in the glomerulus, activated NK cells in interstitial, and resting NK cells were accumulated in tubules in LN. The immune-related function analysis of differential expression proteins in different regions indicated that the glomerulus and interstitial were major sites of immune disturbance and regulation connected with immune response activation. Furthermore, we identified 7, 8, and 9 hub genes in LN's glomerulus, renal interstitial, and tubules. These hub genes were significantly correlated with the infiltration of immune cell subsets. We screened out ALB, CTSB, LCN2, A2M, CDC42, VIM, LTF, and CD14, which show higher performance as candidate biomarkers after correlation analysis with clinical indexes. The function within three regions of the kidney was analyzed. The differential expression proteins (DEGs) between interstitial and glomerulus were significantly enriched in the immune-related biological processes, and myeloid leukocyte-mediated immunity and cellular response to hormone stimulus. The DEGs between tubules and glomerulus were significantly enriched in cell activation and leukocyte-mediated immunity. While the DEGs between tubules and interstitial were enriched in response to lipid, antigen processing, and presentation of peptide antigen response to oxygen-containing compound, the results indicated a different function within kidney regions. CONCLUSIONS: Collectively, we revealed spatial proteomics and immune signature of LN kidney regions by combined using LCM and DIA.

DIALIZE China: A Phase IIIb, Randomized, Placebo-Controlled Study to Reduce Predialysis Hyperkalemia With Sodium Zirconium Cyclosilicate in Chinese Patients.

PURPOSE: The DIALIZE China study (Reduce Incidence of Pre-Dialysis Hyperkalaemia With Sodium Zirconium Cyclosilicate in Chinese Subjects) (NCT04217590) evaluated sodium zirconium cyclosilicate (SZC) for the management of hyperkalemia in Chinese patients undergoing hemodialysis. METHODS: In the double-blind, Phase IIIb DIALIZE China study, Chinese adults with kidney failure and predialysis hyperkalemia (predialysis serum potassium [sK+] concentration >5.4 mmol/L after the long interdialytic interval [LIDI] and >5.0 mmol/L after ≥1 short interdialytic interval) who were receiving hemodialysis 3 times weekly were randomized to placebo or SZC 5 g once daily on nondialysis days. Doses were titrated towards maintaining normokalemia for 4 weeks (titration period) in 5-g increments up to 15 g. Primary efficacy was the proportion of responders during the 4-week evaluation period following the titration period (ie, those with a predialysis sK+ of 4.0-5.0 mmol/L for at least 3 of 4 hemodialysis visits following the LIDI) who did not require urgent rescue therapy. FINDINGS: Overall, 134 adults (mean [SD] age, 55 [11.3] years) were randomized to SZC or placebo (n = 67 each). There were significantly more responders with SZC (37.3%) versus placebo (10.4%; estimated odds ratio [OR] = 5.10; 95% CI, 1.90-15.12; P < 0.001). The probability of all predialysis sK+ concentrations being 3.5 to 5.5 mmol/L was significantly higher with SZC versus placebo (estimated OR = 6.41; 95% CI, 2.71-15.12; P < 0.001). A greater proportion of patients achieved an sK+ of 3.5 to 5.5 mmol/L on at least 3 of 4 LIDI visits during evaluation with SZC (73.1%) versus placebo (29.9%). Serious adverse events occurred in 9.1% and 11.9% of patients in the SZC and placebo groups, respectively. IMPLICATIONS: SZC treatment for predialysis hyperkalemia is effective and well tolerated in Chinese patients with kidney failure receiving hemodialysis. CLINICALTRIALS: gov identifier: NCT04217590.

Astrocytes in the spinal cord contributed to acute stress-induced gastric damage via the gap junction protein CX43.

Rat restraint water-immersion stress (RWIS) is a compound stress of high intensity and is widely used to study the pathological mechanisms of stress gastric ulcers. The spinal cord, as a part of the central nervous system, plays a dominant role in the gastrointestinal tract, but whether the spinal cord is involved in rat restraint water-immersion stress (RWIS)-induced gastric mucosal damage has not been reported. In this study, we examined the expression of spinal astrocytic glial fibrillary acidic protein (GFAP), neuronal c-Fos, connexin 43 (Cx43), and p-ERK1/2 during RWIS by immunohistochemistry and Western blotting. In addition, we intrathecally injected the astrocytic toxin L-a-aminoadipate (L-AA), gap junction blocker carbenoxolone (CBX), and ERK1/2 signaling pathway inhibitor PD98059 to explore the role of astrocytes in the spinal cord in RWIS-induced gastric mucosal damage and its possible mechanism in rats. The results showed that the expression of GFAP, c-Fos, Cx43, and p-ERK1/2 was significantly elevated in the spinal cord after RWIS. Intrathecal injection of both the astrocyte toxin L-AA and the gap junction blocker CBX significantly attenuated RWIS-induced gastric mucosal damage and decreased the activation of astrocytes and neurons induced in the spinal cord. Meanwhile, the ERK1/2 signaling pathway inhibitor PD98059 significantly inhibited gastric mucosal damage, gastric motility and RWIS-induced activation of spinal cord neurons and astrocytes. These results suggest that spinal astrocytes may regulate the RWIS-induced activation of neurons via CX43 gap junctions and play a critical role in RWIS-induced gastric mucosa damage through the ERK1/2 signaling pathway.

Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.

The characteristics of extrachromosomal circular DNA in patients with end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is the final stage of chronic kidney disease (CKD). In addition to the structurally intact chromosome genomic DNA, there is a double-stranded circular DNA called extrachromosomal circular DNA (eccDNA), which is thought to be involved in the epigenetic regulation of human disease. However, the features of eccDNA in ESRD patients are barely known. In this study, we identified eccDNA from ESRD patients and healthy people, as well as revealed the characteristics of eccDNA in patients with ESRD. METHODS: Using the high-throughput Circle-Sequencing technique, we examined the eccDNA in peripheral blood mononuclear cells (PBMCs) from healthy people (NC) (n = 12) and ESRD patients (n = 16). We analyzed the length distribution, genome elements, and motifs feature of eccDNA in ESRD patients. Then, after identifying the specific eccDNA in ESRD patients, we explored the potential functions of the target genes of the specific eccDNA. Finally, we investigated the probable hub eccDNA using algorithms. RESULTS: In total, 14,431 and 11,324 eccDNAs were found in the ESRD and NC groups, respectively, with sizes ranging from 0.01 kb to 60 kb at most. Additionally, the ESRD group had a greater distribution of eccDNA on chromosomes 4, 11, 13, and 20. In two groups, we also discovered several motifs of specific eccDNAs. Furthermore, we identified 13,715 specific eccDNAs in the ESRD group and 10,585 specific eccDNAs in the NC group, both of which were largely annotated as mRNA catalog. Pathway studies using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the specific eccDNA in ESRD was markedly enriched in cell junction and communication pathways. Furthermore, we identified potentially 20 hub eccDNA-targeting genes from all ESRD-specific eccDNA-targeting genes. Also, we found that 39 eccDNA-targeting genes were associated with ESRD, and some of these eccDNAs may be related to the pathogenesis of ESRD. CONCLUSIONS: Our findings revealed the characteristics of eccDNA in ESRD patients and discovered potentially hub and ESRD-relevant eccDNA-targeting genes, suggesting a novel probable mechanism of ESRD.

The clinical efficacy of fluticasone propionate combined with ACEI/ARB in the treatment of immunoglobulin A nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide, and lacks the effective treatment. The study was aimed to investigate the clinical efficacy of fluticasone propionate aerosol combined with angiotensin converting enzyme inhibitor / angiotensin receptor blocker (ACEI/ARB) in the treatment of IgAN. METHODS: 142 patients with biopsy-proven IgAN at Shenzhen People?s hospital from June 2018 to June 2020 were enrolled. The patients were randomly divided into the supportive care plus fluticasone group and the supportive care group. The patients of the supportive care plus fluticasone group were treated with fluticasone propionate aerosol (250 ?g Bid) combined with ACEI/ARB, while the supportive care group was merely treated with ACEI/ARB. The patients were followed up at 3, 6 and 9 months after enrollment. Primary outcomes include changes in proteinuria and estimated glomerular filtration rate (eGFR). RESULTS: The level of proteinuria in the supportive care plus fluticasone group was significantly lower compared with the supportive care group at 0, 3, 6 and 9 months. Meanwhile, during the follow-up period, no serious adverse events were recorded during the study in either group. However, fluticasone treatment did not alleviate the decline in eGFR. CONCLUSION: Fluticasone propionate aerosol combined with ACEI/ARB can reduce the level of proteinuria in thetreatment of IgAN, and has no significant effects on renal function.

Role of symbiotic microbiota dysbiosis in the progression of chronic kidney disease accompanied with vascular calcification.

Background: Chronic kidney disease (CKD) is now globally recognized as a critical public health concern. Vascular calcification (VC) represents a significant risk factor for cardiovascular events in individuals with CKD. It is the accessible and precise diagnostic biomarkers for monitoring the progression of CKD and the concurrent VC are urgently needed. Methods: The adenine diet-induced CKD rat model was utilized to investigate chronic kidney injury, calcification in the kidney and thoracic aorta, and dysregulation of biochemical indices. Enzyme-linked immune sandwich assays were employed to analyze changes in calcification-related proteins. 16S rRNA sequencing was performed to delineate the microbiota characteristics in the gut and blood of CKD-afflicted rats. Additionally, transcriptome sequencing of kidney tissue was conducted to explore the relationship between CKD-associated microbiota features and alterations in kidney function. Results: The adenine diet-induced CKD inhibited body weight gain, and led to kidney injury, and pronounced calcification in kidney and thoracic aorta. The microbiota both in the gut and blood of these affected rats exhibited significantly lower alpha diversity and distinctive beta diversity than those in their healthy counterparts. CKD resulted in dysregulation of several biochemical indices (including elevated levels of creatinine, low-density lipoprotein-cholesterol, sodium, phosphorous, total cholesterol, and urea and decreased levels of albumin, calcium, lactate dehydrogenase, and total bilirubin). Moreover, it upregulated calcification-related factors (bone sialoprotein [BSP], Klotho, fibroblast growth factor [FGF]-23, and sclerostin [SOST]) and lipopolysaccharide (LPS). Notably, the increased Acinetobacter in the blood was positively associated with calcifications in the kidney and thoracic aorta, in addition to the positive correlation with gut microbiota. The enrichment of Acinetobacter was concurrent with increases in calcification factors (BSP, FGF-23, and SOST), LPS, and phosphorous. Furthermore, transcriptome sequencing revealed that the enrichment of Acinetobacter was positively correlated with the majority of upregulated genes and negatively correlated with downregulated genes involved in the mineral absorption pathway. Conclusion: Our findings, for the first time, underscore that dysbiosis of symbiotic microbiota, both in the gut and blood, is involved in the progression of CKD. Particularly, the enrichment of Acinetobacter in blood emerges as a potential risk factor for CKD and its accompanying VC.

Ventromedial hypothalamus relays chronic stress inputs and exerts bidirectional regulation on anxiety state and related sympathetic activity.

Chronic stress can induce negative emotion states, including anxiety and depression, leading to sympathetic overactivation and disturbed physiological homeostasis in peripheral tissues. While anxiety-related neural circuitry integrates chronic stress information and modulates sympathetic nervous system (SNS) activity, the critical nodes linking anxiety and sympathetic activity still need to be clarified. In our previous study, we demonstrated that the ventromedial hypothalamus (VMH) is involved in integrating chronic stress inputs and exerting influence on sympathetic activity. However, the underlying synaptic and electrophysiological mechanisms remain elusive. In this study, we combined in vitro electrophysiological recordings, behavioral tests, optogenetic manipulations, and SNS activity analyses to explore the role of VMH in linking anxiety emotion and peripheral SNS activity. Results showed that the VMH played an important role in bidirectionally regulating anxiety-like behavior and peripheral sympathetic excitation. Chronic stress enhanced excitatory inputs into VMH neurons by strengthening the connection with the paraventricular hypothalamus (PVN), hence promoting anxiety and sympathetic tone outflow, an important factor contributing to the development of metabolic imbalance in peripheral tissues and cardiovascular diseases.

Microbiome and metabolome analysis to clarify the interaction between the urine microbiota and serum metabolites in Chinese patients with immunoglobulin A nephropathy.

Background: The bacterial and metabolic networks in immunoglobin A nephropathy (IgAN), the most common type of primary chronic glomerulonephritis worldwide, have not been extensively studied. To help develop better methods for the diagnosis, treatment, and prognosis of IgAN, we characterized the alterations of the urinary microbiome and serum metabolome in patients with IgAN. Methods: We analyzed serum and urine samples from Chinese patients with IgAN and healthy controls (HCs) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 16S ribosomal RNA gene sequencing. Results: Patients with IgAN had a higher relative abundance of Actinomyces and a lower relative abundance of Lactobacillus. The elements of metabolism have been affected, including free amino acids, polyunsaturated fatty acids, and oligopeptides. We also identified the 9 metabolites that might be the core metabolites, including guanidinoacetic acid, apo-[3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)], and diethanolamine, which linked the metabolic networks between the urinary tract (UT) and blood. Other core metabolites, such as homocitrulline, apo-[3-methylcrotonoyl-CoA:carbon-dioxide ligase (ADP-forming)], butyrylcarnitine, formiminoglutamic acid (FIGLU), diethanolamine, and prolylhydroxyproline, were positively correlated with urinary mili-total protein (MTP). Conversely, Lactobacillus was negatively correlated with MTP. Conclusions: We verified the connection between the disruption of the microbiota and serum metabolites, along with the clinical parameters, in patients with IgAN, which may help provide a tool for IgAN interventions.

IgA nephropathy with mimicking Fabry disease: A case report and literature review.

BACKGROUND: Fabry disease (FD) is a rare, inherited disease lysosomal storage disorder caused by the lack of an alpha-galactosidase enzyme. This genetic disease can affect both men and women. The understanding of FD is very important as this condition can be effectively treated. For women who may exhibit normal residual enzyme activity, the diagnosis is more challenging. CASE PRESENTATION: Herein, we reported on a case of IgA nephropathy and renal disease that mimicked FD in a female patient. The presence of zebra bodies in the cytoplasm of glomerular podocytes is widely accepted as a hallmark pathological manifestation of FD. In the present case, renal biopsy analysis revealed the presence of zebra bodies; however, genetic testing indicated that the patient did not have FD. The mechanisms and causes of zebra body formation remained unclear in the present case. However, the patient responded well to treatment with an angiotensin receptor blocker. CONCLUSIONS: The reported findings can be useful for the differential diagnosis of FD and renal diseases in the future. Our results also highlight the clinical significance of zebra bodies in renal disease.

A comprehensive investigation discovered the novel methyltransferase METTL24 as one presumably prognostic gene for kidney renal clear cell carcinoma potentially modulating tumor immune microenvironment.

Background: Recently, an increasing number of studies have uncovered the aberrant expression of methyltransferase-like family (METTL) plays an important role in tumorigenesis, such as METTL3 (an m6A writer). In our recent work, we discovered METTL24 expression was highly associated with the hazard ratio (HR) of kidney renal clear cell carcinoma (KIRC) compared to other tumors, implying a special function of METTL24 in KIRC carcinogenesis. Until now, the functions and mechanisms of METTL24 in KIRC have remained mostly unknown. Methods: The mRNA expression of METTL24 in KIRC was analyzed using the TIMER 2.0, GEPIA, and UALCAN databases. The immunohistochemical assay was performed to validate METTL24 expression in our self-built Chinese cohort (n tumor = 88, n normal = 85). The gene set enrichment analysis (GSEA) was used to investigate the biological processes in which METTL24 might be engaged. The Spearman analysis was used to evaluate the expression correlations between METTL24 and a range of immunological variables, and the effects of METTL24 on the infiltration levels of multiple immune cells were explored using TCGA data. The upstream transcription factors of METTL24 were screened through a multi-omics analysis. Results: METTL24 expression in KIRC tissues was significantly decreased compared to normal adjacent kidney tissues, which was associated with the lower survival rate of KIRC patients. METTL24 potentially participated in the immune-relevant biological processes such as cytokine binding, NF-kappa B binding, MHC protein complex, and interleukin-12 action. Besides, METTL24 expression was linked to a number of immune checkpoints, cytokines, chemokines, and chemokine receptors, and also correlated with the infiltration levels of 10 types of immune cells in KIRC. Meanwhile, METTL24 expression differently affected the overall survival rates (OS) of KIRC patients with high or low levels of immune infiltration. Finally, CTCF and EP300 were discovered to be the probable transcription factors of METTL24 in KIRC. Conclusion: This study revealed that METTL24 might serve as a prognostic marker in KIRC and as one immune-relevant target for clinical treatment.