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To predict the risk factors for cardiovascular events within 5 years in patients with peritoneal dialysis-associated peritonitis and establish a nomogram for clinical prediction. A prediction model was established by conducting an observational study in 150 patients with peritoneal dialysis-associated peritonitis obtained from the Information Database of AnHui Medical University Affiliated Hospital. The nomogram was constructed using the multivariate COX regression model. The C-index and the calibration plot were used to assess the discrimination and calibration of the prediction model. The elderly [HR = 2.453 (1.071–5.619)], history of cardiovascular events [HR = 2.296 (1.220–4.321)], alkaline phosphatase [HR = 1.004 (1.002–1.005)] and culture-positive [HR= 2.173 (1.009–4.682)] were identified as risk predictors of cardiovascular events, while serum albumin [HR = 0.396(0.170–0.924)] was identified as protective predictors of cardiovascular events. Combined with clinical studies, we constructed a nomogram based on the minimum value of the Akaike Information Criterion or Bayesian Information Criterion. The C index of the nomogram is 0.732, revealing great discrimination and appropriate calibration. Through the total score of the nomogram and the result of ROC, we classify patients into high-risk groups (cardiovascular events group) and low-risk groups (no cardiovascular events group). Cardiovascular events were significantly different for patients in the high-risk group compared to the low-risk group (HR = 3.862(2.202–6.772; p < 0.001). The current novel nomogram can accurately predict cardiovascular events in patients with peritonitis associated with peritoneal dialysis. However, external validation is required before the model can be used in clinic settings. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease (DKD) is closely associated with the death or survival of resident kidney cells. Aim: The purpose of this study was to determine the changes in renal cell survival and death in DKD and their diagnostic values in DKD progression. Materials and Methods: This study analyzed a dataset of renal tissues from DKD patients to identify changes in genes associated with renal cell death and survival. Our findings were subsequently validated in human kidney tissues. Differential indicators of DKD patients' clinicopathological data screened by stepwise regression and glomerular P62 protein expression were included in binary logistic regression analysis to assess the impact of these parameters on DKD progression. A receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic value of P62 protein in DKD progression. Results: Bioinformatics analysis results revealed that glomerular autophagy in DKD was more significantly altered, which was consistent with the semi-quantitative results of P62 in glomeruli. Further studies established that P62 expression was mainly increased in podocytes. Stepwise regression analysis indicated that changes in the expressions of glomerular P62 and apolipoprotein A1 (ApoA1) might be involved in the progression of DKD. However, binary logistic regression analysis results suggested that only P62 was significantly associated with DKD development. ROC curve analysis showed that the area under the curve (AUC) of P62 for the detection of DKD was 0.905. Conclusion: Autophagy inhibition occurred in both glomeruli and tubules, and was most pronounced in glomerular podocytes. The levels of P62 protein in glomeruli, as an autophagy activity indicator, was one of the predictors of entering the stage of macroalbuminuria in DKD. Graphical [ABSTRACT FROM AUTHOR]

To investigate the predictors of coronary artery calcification (CAC) and its association with cardiovascular events (CVE) in patients with stage 3–5 chronic kidney disease (CKD). Two hundred ninety CKD patients in our nephrology department were enrolled from 2018 to May 2019. The levels of matrix Gla protein (MGP) and interleukin 6 (IL-6) were measured via enzyme-linked immunosorbent assay (ELISA) method in 131 CKD patients of all. CAC was evaluated via computed tomography (CT). The covariate factors were analyzed by binary logistic regression analysis. We conducted the visits to explore the prevalence of CVE in 276 CKD patients, and covariate factors were analyzed by Cox proportional hazard model. The prevalence of CAC was up to 57.93%. We found that age, diabetes mellitus, hyperphosphatemia, dialysis duration, and the neutrophil-lymphocyte ratio (NLR) were positively associated with CAC in all patients. In 131 patients, we demonstrated that higher IL-6 and lower MGP levels were associated with CAC. A Cox proportional hazard model demonstrated that moderate to severe CAC was correlated with an increased risk for CVE [Hazard Ratio (HR): 7.250; 95% confidence interval (CI): 3.192–16.470], and a higher MGP level was associated with a reduced risk for CVE (HR: 0.340; 95% CI: 0.124–0.933). The prevalence of CAC in patients with CKD is a significant issue. Older age, hyperphosphatemia, dialysis duration, diabetes mellitus, IL-6, and the NLR are associated with CAC. In addition, higher MGP levels represent protective factor for CAC. Moderate to severe CAC, and lower MGP levels are associated with an increased risk for CVE. Abbreviations: AGEs: Advanced glycosylation end products; CAC: Coronary artery calcification; CACS: Coronary artery calcification score; Ca: Calcium; CI: confidence interval; CKD: Chronic kidney disease; CVE: Cardiovascular events; CT: Computed tomography; ELISA: Enzyme-linked immunosorbent assay; Hb: hemoglobin; HR: Hazard ratio; hs-CRP: high-sensitivity C-reactive protein; IL-6: Interleukin 6; iPTH: Intact parathyroid hormone; Mg: Magnesium; MGP: Matrix Gla protein; NF-κB: nuclear factor-kappa gene binding; NRL: Neutrophil-lymphocyte ratio; Runx2: Runt-related transcription factor 2; RRT: Renal replacement therapy; P: Phosphorus; Scr: Serum creatinine; TNF--alpha: Tumor necrosis factor--alpha; TC: Total cholesterol; TG: Triglyceride; VSMC: vascular smooth muscle cel [ABSTRACT FROM AUTHOR]

To investigate the relationship between preoperative proteinuria and postoperative acute kidney injury (AKI). We performed a search on databases included PubMed, Embase, the Cochrane Library, and Web of Science, from December 2009 to September 2020. Data extracted from eligible studies were synthesized to calculate the odds ratio (OR) and 95% confidence interval (CI). A fixed or random effects model was applied to calculate the pooled OR based on heterogeneity through the included studies. This meta-analysis of 11 observational studies included 203,987 participants, of whom 21,621 patients suffered from postoperative AKI and 182,366 patients did not suffer from postoperative AKI. The combined results demonstrated that preoperative proteinuria is an independent risk factor for postoperative AKI (adjusted OR = 1.65, 95%CI:1.44–1.89, p < 0.001). Subgroup analysis showed that both preoperative mild proteinuria (adjusted OR = 1.30, 95%CI:1.24–1.36, p < 0.001) and preoperative heavy proteinuria (adjusted OR = 1.93, 95%CI:1.65–2.27, p < 0.001) were independent risk factors for postoperative AKI. The heterogeneity was combined because its values were lower. Further subgroup analysis found that preoperative proteinuria measured using dipstick was an independent risk factor for postoperative AKI (adjusted OR = 1.48, 95%CI:1.37–1.60, p < 0.001). Finally, preoperative proteinuria was an independent risk factor for postoperative AKI in the non-cardiac surgery group (adjusted OR = 2.06, 95%CI:1.31–3.24, p = 0.002) and cardiac surgery group (adjusted OR = 1.69, 95%CI:1.39–2.06, p < 0.001) Preoperative proteinuria is an independent risk factor for postoperative AKI and in instances when proteinuria is detected using dipsticks. [ABSTRACT FROM AUTHOR]

Purpose: To date, the prevalence and prognostic role of coronary artery calcification (CAC) in patients with chronic kidney disease (CKD) have been investigated in several studies, but have yielded conflicting results. The aim of this meta-analysis is to derive a more precise estimation of CAC prevalence in CKD patients and its association with cardiovascular events and mortality. Methods: The relevant literature was identified and evaluated from inception until July 2018 through multiple search strategies on PubMed, Embase, and Web of Science. Cross-sectional or cohort (baseline data) studies reporting CAC prevalence were included. Data extracted from eligible studies were used to calculate effect estimates (ESs) and 95% confidence intervals (95%CI). We searched databases for observational studies that explored baseline CAC and subsequent cardiovascular or all-cause mortality risk in CKD patients. Results: The meta-analysis included 47 studies; 38 of these were included in the final analysis of CAC prevalence. The pooled prevalence of CAC in random effect model was 60% (95%CI 53–68%). CAC was positively associated with an increased risk of all-cause mortality (hazard ratio [HR] 3.44; 95%CI 2.40–4.94), cardiovascular mortality (HR 3.87; 95%CI 2.06–7.26), and cardiovascular events (HR 2.09; 95%CI 1.19–3.67), when comparing individuals in the top CAC score group to those in the bottom CAC score group. Conclusions: The pooled prevalence of CAC is highly prevalent. CAC is independently associated with all-cause and cardiovascular mortality risk as well as cardiovascular events among CKD patients. In view of the high heterogeneity, larger clinical trials are still needed. [ABSTRACT FROM AUTHOR]

Paeoniflorin (PF) is the primary component of total glucosides of paeony (TGP). It exerts multiple effects, including immunoregulatory and anti-inflammatory effects. Our previous study has found that PF has a remarkable renal-protective effect in diabetic mice, but exact mechanism has not been clarified. This study mainly explores whether PF affects macrophage infiltration and activation in diabetic kidney through TLR4 pathway. Thus, this study was conducted to investigate the effect of PF on a streptozotocin (STZ)-induced experimental DN model. The results suggested that the onset and clinical symptoms of DN in mice were remarkably ameliorated after the administration of PF. Moreover, the number of infiltrating macrophages in the mouse kidneys was also markedly decreased. Instead of inhibiting the activation of macrophages directly, PF could influence macrophages by suppressing iNOS expression as well as the production of TNF-α, IL-1β, and MCP-1 both in vivo and in vitro. These effects might be attributable to the inhibition of the TLR4 signaling pathway. The percentage of M1-phenotype cells as well as the mRNA levels of iNOS, TNF-α, IL-1β, and MCP-1 were downregulated when PF-treated polarized macrophages were cultured under conditions of high glucose (HG) levels. In addition, the expression of TLR4, along with that of downstream signaling molecule proteins, was also reduced. Our study has provided new insights into the potential of PF as a promising therapeutic agent for treating DN and has illustrated the underlying mechanism of PF from a new perspective. [ABSTRACT FROM AUTHOR]

Background/Aims: To estimate the clinical value of bacterial detection in peritoneal dialysis-associated peritonitis (PDAP) by multiplex real-time polymerase chain reaction (RT-PCR). This study was undertaken to evaluate multiplex RT-PCR for identifying clinically significant bacteria in PDAP. Methods: Seventy peritoneal dialysate specimens were collected and traditional bacterial culture and universal primer RT-PCR detection of the bacterial were used. Results: The positive rate of traditional culture method was 65.71% (46/70) and that of universal primer RT-PCR was 81.42% (57/70). For 6 clinical commonly pathogenic bacteria, multiplex, and monoplex RT-PCR all detected 38 positive ones within the 57 specimens that were detected positive by universal primer RT-PCR. The results of the 2 methods were completely identical. Detecting bacteria by universal primer PCR and Monoplex RT-PCR needs 4–5 and 6–9 h, respectively, while multiplex RT-PCR needs less than 3 h. Conclusion: Our results demonstrated that the multiplex RT-PCR can detect several kinds of bacteria simultaneously and it is also more practical and convenient than monoplex RT-PCR. [ABSTRACT FROM AUTHOR]

This study is to investigate the associations between apolipoprotein E (ApoE) gene polymorphisms and cardiovascular complications of uremic patients on maintenance hemodialysis (MHD). Uremic patients on MHD (189, case group) and healthy people (165, control group) were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to test ApoE gene polymorphisms. Indicators of MHD and cardiovascular complications were observed. Compared with the control group, the case group had decreased frequency of ε3/3 genotype and ε3 allele and increased ε4/3 genotype and ε4 allele. The ε4 group had elevated adiponectin, serum creatinine, blood urea nitrogen, and total cholesterol but decreased HDL-C compared with other groups. The ε3 group had reduced complications. ApoE ε3 and ε4 alleles were related with cardiovascular complications of the uremic patients on MHD. We concluded that ApoE gene polymorphisms were associated with susceptibility to infections in uremia, and that ApoE ε3 and ε4 alleles might correlate with cardiovascular complications of uremic patients on MHD. [ABSTRACT FROM AUTHOR]

Context:Total glucosides of peony (TGP), compounds extracted from the dried roots ofPaeonia lactifloraPall, have been reported to have anti-inflammatory and antioxidative activities. However, the protective effect of TGP on liver injury and the underlying mechanisms remains unknown in diabetic rats. Objectives:Current study investigates prevention of liver injury by TGP in diabetic rats and its mechanism was related to the inhibition of endoplasmic reticulum stress (ERS). Materials and methods:Fifty adult male rats were randomly divided into: Normal group, diabetic group, TGP (50, 100 and 200 mg/kg/day) treatment groups (n = 10 per group). At the end of the 8th week, the liver was removed for biochemical and histological examinations. Results:Compared with the diabetic group, administration of TGP at doses of 50, 100 and 200 mg/kg significantly prevented the increase of hepatic fibrosis score (ED50139.4 mg/kg). Compared with diabetic group, TGP at doses of 50, 100 and 200 mg/kg showed an inhibition on the increased macrophage infiltration. MCP-1 and TNF-α mRNA and protein expression were significantly increased in diabetic group compared with normal group; TGP administration caused significant reduction of high levels of MCP-1 and TNF-α mRNA as well as protein levels. Also, TGP at all doses showed an inhibition on the increased GRP78 levels, p-Perk levels and p-Eif2α levels in liver from diabetic group. Discussion and conclusions:Our results indicate that TGP has potential as a treatment for diabetic liver injury attenuating liver lipid accumulation and inflammation as well as ERS induced by diabetic condition. [ABSTRACT FROM PUBLISHER]

Objective: Vitamin D (VD) deficiency is an independent risk factor for cognitive impairment (CI) in the general population, but VD status in peritoneal dialysis (PD) patients has not been investigated. In this study, we aimed to investigate the relationship between serum VD levels and global and specific cognitive functions in PD patients. Design and Setting: Cross-sectional study, simultaneously conducted at two PD centers. Patients: Clinically stable patients (n = 273) undergoing PD for at least 3 months were enrolled over a period of one year. Main outcome Measures: Demographic and comorbidity data were recorded, and routine biochemical parameters and serum 25-hydroxyvitamin D (25(OH) D) levels of overnight fasted patients were determined. Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MS) score; executive function, by the trail making tests (Trails A and B); and immediate memory, delayed memory, and language ability by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) sub-tests. Results: In the univariate analysis, serum 25(OH) D levels significantly correlated with 3MS scores (r = -0.139; P = 0.02), and Trail A (r = -0.188; P = 0.002) and B (r = -0.154; P = 0.01) completion times. In the multivariate analysis, 25(OH) D was found to be independently associated with global CI, but not with executive dysfunction. Serum 25(OH) D could not predict scores of immediate/delayed memory and language ability. Conclusions: VD deficiency is highly prevalent in PD patients and is an independent risk factor for global CI in this patient cohort. [ABSTRACT FROM AUTHOR]

Background: We investigated whether urinary mRNA of connective tissue growth factor (CCN2) and nephroblastoma overexpressed gene (CCN3) can provide clinical insight into the management of patients with nondiabetic CKD. Methods: Urinary mRNA expression of CCN2 and CCN3 were measured by Real-time PCR in 35 CKD patients and 12 controls. Results: Urinary mRNA of CCN2 and CCN3 were distinctively greater in CKDs than healthy controls. Urinary CCN3/CCN2 mRNA ratio correlated to the degree of glomerular histological changes in those who received renal biopsy. Conclusion: Urinary CCN3/CCN2 mRNA ratio may be a useful noninvasive biomarker for evaluating patients with nondiabetic CKD prior to renal biopsy. [ABSTRACT FROM AUTHOR]

Total glucosides of paeony (TGP) is the major active constituent of Paeonia lactiflora Pall., which has shown renoprotection in experimental diabetic nephropathy. Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage. Macrophages also play an essential role in the pathogenesis of diabetic nephropathy. Herein, we investigated the ability of TGP to modulate JAK2/STAT3 activation and macrophage proliferation in rats with streptozotocin (STZ)-induced diabetes. TGP (50, 100, and 200 mg/kg) was administered orally once a day for eight weeks. Levels of p-JAK2 and p-STAT3 were determined by Western blot analysis. Immunohistochemistry and double immunohistochemistry were used to identify p-STAT3, ED-1, PCNA/ED-1, and p-STAT3/ED-1-positive (+) cells. The elevated 24-h urinary albumin excretion rate was markedly attenuated by treatment with 50, 100, and 200 mg/kg TGP. Western blot analysis showed that the significantly increased levels of p-JAK2, p-STAT3 proteins in the kidneys of diabetic rats were significantly inhibited by 50, 100, and 200 mg/kg TGP treatment. The marked accumulation and proliferation of macrophages in diabetic kidneys were significantly inhibited by TGP treatment. ED-1+/p-STAT3+ cells were significantly increased in the kidneys from the model group but were significantly inhibited by TGP treatment. These results show that TGP significantly inhibited diabetic nephropathy progression and suggest that these protective effects are associated with the ability of TGP to inhibit the JAK2/STAT3 pathway and macrophage proliferation and action. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Paeoniflorin(PF), extracted from the root peeled of Paeonia lactiflora Pall(Family: Ranunculaceae), has therapeutic potential in many animal models of inflammatory diseases. Aim of the study Although the anti-inflammatory efficacy of PF has been well illustrated in several animal models, whether it could attenuate diabetic nephropathy and detailed mechanisms are still obscure. Till now, accumulating evidence has proposed the pivotal role of toll-like receptors (TLRs) in renal inflammation in diabetic patients. In this setting, the current study aimed to investigate the effects and underlying mechanism of PF on high glucose-induced activation of toll like-receptor 2 (TLR2) signaling in macrophages. Materials and methods Bone marrow-derived macrophages (BMDM) were isolated from male Tlr2 tm1kir (TLR2-/-) mice and wild-type littermates (C57BL/6JWT). The level of TLR2 and activation of downstream signaling were evaluated in response to 30 mmol/L high glucose (HG)-containing medium. Macrophages behaviors, which include cell viability, migration and inflammatory cytokines production, were also determined. Results PF suppressed HG-induced production of TLR2, activation of downstream signaling and synthesis of inducible nitric oxide synthase (iNOS). PF could further inhibit MyD88-dependent pathway in HG-induced models in which TLR2 was knocked out. Moreover, deletion of TLR2 inhibited the HG-induced activation of MyD88-dependent pathway, but not TIR domain containing adapter inducing interferon-β (Trif) signal pathway in BMDMs. As HG stimulation polarizes macrophages into M1 phenotype, treatment of PF or knockout of TLR2 significantly reduces M1 markers on the membrane of macrophages. Additionally, levels of inflammatory cytokines and iNOS were remarkably reduced in response to PF or TLR2 deficiency. Conclusion Collectively, these data demonstrated that HG activated macrophages primarily through TLR2-dependent mechanisms which aggravated the severity of renal inflammation and eventually contributed to DN. Additionally, PF might be applied as a potential therapeutic agent in the battle against progressive DN. [ABSTRACT FROM AUTHOR]

• Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors and there is still no effective treatment for AKI. • A novel small molecule Hsp90 inhibitor, C-316-1, prevented necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced in vitro and in vivo via binding with R46, E47 and S50 in Cdc37 binding site of Hsp90. • C-316-1 is a novel Hsp90 inhibitor with high efficiency in treatment of AKI and Hsp90 may serve as a potential therapeutic target for AKI. Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors. Recently, although our group found that PPBICA alleviated programmed cell death in AKI, poor water solubility limited its bioavailability. In this research, we screened a series of derivatives and found that C-316-1 had the best suppressive effect on preventing necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced AKI in vitro and in vivo with lower toxicity and better water solubility. Mass spectrometry results showed that C-316-1 bound to heat shock protein 90 (Hsp90), which was further confirmed by molecular docking and surface plasmon resonance. Additionally, the Hsp90 expression was upregulated in the blood and tissues of AKI patients. We discovered that C-316-1 decreased the RIPK1 protein level without affecting its mRNA expression. The proteasome inhibitor, MG132 restored the level of RIPK1 reduced by C-316-1, suggesting that C-316-1 limits necroptosis by promoting the degradation of RIPK1 rather than by reducing its production. Immunoprecipitation further showed that pretreatment with C-316-1 disrupted the Hsp90-Cdc37 protein–protein Interactions (PPIs). Thereby, C-316-1 inhibited the Hsp90-Cdc37 complex formation and led to a significant decrease in RIPK1, which in turn reduced necroptosis. Moreover, C-316-1 treatment did not protect against kidney injury in vivo and in vitro when Hsp90 was knocked down and R46, E47, and S50 in Cdc37 binding site of Hsp90 might form an important active pocket with C-316-1. These findings suggest that C-316-1 is a potential therapeutic agent against RIPK1-Mediated Necroptosis in AKI. [ABSTRACT FROM AUTHOR]

• M2 phenotype macrophages (CD163+) were dominant in human lupus nephritis. • Correlation was seen among CD163+ macrophages, crescents, and complement activation. • C3aR co-localized with CD163 and correlated with crescents. • C3aR induced macrophages to polarize to an M2 phenotype. The function of the complement and macrophage crosstalk during the formation of crescents in lupus nephritis has not yet been reported. This study therefore aimed to explore the association of crescents, complements, and M2 macrophages with clinical features in lupus nephritis. We assessed a Chinese cohort comprising 301 patients with lupus nephritis. Renal biopsy specimens were collected from 64 patients with proliferative lupus nephritis (class III/III + V or IV/IV + V). The renal deposition of cluster of differentiation (CD) 68, inducible nitric oxide synthase, CD163, and C3a receptor (C3aR) was evaluated by immunostaining. The associations among crescents, complements, and M2 macrophages were also analyzed. Next, the underlying mechanism was investigated in vitro using C3a-treated macrophages. We found that M2-phenotype macrophages (CD163+) were the dominant subpopulation in human lupus nephritis. Additionally, a significant association was observed among the CD163+ macrophages, crescents, and complement activation. C3aR co-localized with CD163 and correlated with crescents and could induce polarization of macrophages to an M2 phenotype. Overall, these results suggest that complement-mediated M2/M1 macrophage polarization may contribute to the formation of crescents in lupus nephritis. [ABSTRACT FROM AUTHOR]

Alcohol consumption is one of the risk factors for kidney injury. The underlying mechanism of alcohol-induced kidney injury remains largely unknown. We previously found that the kidney in a mouse model of alcoholic kidney injury had severe inflammation. In this study, we found that the administration of alcohol was associated with the activation of NLRP3 inflammasomes and NF-κB signaling, and the production of pro-inflammatory cytokines. Whole-genome methylation sequencing (WGBS) showed that the DNA encoding fat mass and obesity-associated protein (FTO) was significantly methylated in the alcoholic kidney. This finding was confirmed with the bisulfite sequencing (BSP), which showed that alcohol increased DNA methylation of FTO in the kidney. Furthermore, inhibition of DNA methyltransferases (DNMTs) by 5-azacytidine (5-aza) reversed alcohol-induced kidney injury and decreased the mRNA and protein levels of FTO. Importantly, we found that FTO, the m6A demethylase, epigenetically modified peroxisome proliferator activated receptor-α (PPAR-α) in a YTH domain family 2 (YTHDF2)-dependent manner, which resulted in inflammation in alcoholic kidney injury models. In conclusion, our findings indicate that alcohol increases the methylation of PPAR-α m6A by FTO-mediated YTHDF2 epigenetic modification, which ultimately leads to the activation of NLRP3 inflammasomes and NF-κB-driven renal inflammation in the kidney. These findings may provide novel strategies for preventing and treating alcoholic kidney diseases. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI), characterized by a rapid decline in renal function, is triggered by an acute inflammatory response that leads to kidney damage. An effective treatment for AKI is lacking. Using in vitro and in vivo AKI models, our laboratory has identified a series of anti-inflammatory molecules and their derivatives. In the current study, we identified the protective role of rutaecarpine (Ru) on renal tubules. We obtained a series of 3-aromatic sulphonamide-substituted Ru derivatives exhibiting enhanced renoprotective and anti-inflammatory function. We identified Compound-6c(Cpd-6c) as having the best activity and examined its protective effect against cisplatin nephropathy both in vivo and in vitro in cisplatin-stimulated tubular epithelial cells (TECs). Our results showed that Cpd-6c restored renal function more effectively than Ru, as evidenced by reduced blood urea nitrogen and serum creatinine levels in mice. Cpd-6c alleviated tubular injury, as shown by PAS staining and molecular analysis of kidney injury molecule-1 (KIM-1), with both prevention and treatment protocols in cisplatin-treated mice. Moreover, Cpd-6c decreased kidney inflammation, oxidative stress and programmed cell death. These results have also been confirmed in cisplatin-treated TECs. Using web-prediction algorithms, molecular docking, and cellular thermal shift assay (CETSA), we identified phosphodiesterase 4B (PDE4B) as a Cpd-6c target. In addition, we firstly found that PDE4B was up-regulated significantly in the serum of AKI patients. After identifying the function of PDE4B in cisplatin-treated tubular epithelial cells by siRNA transfection or PDE4 inhibitor rolipram, we showed that Cpd-6c treatment did not protect against cisplatin-induced injury in PDE4B knockdown TECs, thus indicating that Cpd-6c exerts its renoprotective and anti-oxidative effects via the PDE4B-dependent pathway. Collectively, Cpd-6c might serve as a potential therapeutic agent for AKI and PDE4B may be highly involved in the initiation and progression of AKI. [ABSTRACT FROM AUTHOR]

Ethnopharmacological Relevance: Paeoniflorin (PF) was found to exhibit renal protection from diabetic kidney disease (DKD) in previous trials, but its specific mechanism remains to be elucidated., Aim of the Study: This study furtherly explored the specific mechanism of PF in protect podocyte injury in DKD., Materials and Methods: We observed the effects of PF on renal tissue and podocytes in DKD by constructing the vitro and vivo models after measuring the pharmacokinetic characteristics of PF. Target proteins of PF were found through target prediction, and verified by molecular docking, CESTA, and SPR, and then furtherly explored the downstream regulation mechanism related to podocyte autophagy and apoptosis by network prediction and co-immunoprecipitation. Finally, by using the target protein inhibitor in vivo and knocking down the target protein gene in vitro, it was verified that PF played a role in regulating autophagy and apoptosis through the target protein in diabetic nephropathy., Results: This study found that in STZ-induced mice model, PF could improve the renal biochemical and pathological damage and podocyte injure (p < 0.05), upregulate autophagy activity (p < 0.05), but inhibit apoptosis (p < 0.01). Vascular endothelial growth factor receptor 2 (VEGFR2), predicted as the target of PF, directly bind with PF reflected by molecular docking and surface plasmon resonance detection. Animal studies demonstrated that VEGFR2 inhibitors have a protective effect similar to that of PF on DKD. Network prediction and co-immunoprecipitation further confirmed that VEGFR2 was able to bind PIK3CA to regulate PI3K-AKT signaling pathway. Furthermore, PF downregulated the phosphorylation of PI3K and AKT (p < 0.05). In vitro, similarly to autophagy inhibitors, PF was also found to improve podocyte markers (p < 0.05) and autophagy activity (p < 0.05), decrease caspase 3 protein (p < 0.05) and further inhibited VEGFR2-PI3K-AKT activity (p < 0.05). Finally, the results of VEGFR2 knockdown were similar to the effect of PF in HG-stimulated podocytes., Conclusion: In conclusion, PF restores autophagy and inhibits apoptosis by targeting the VEGFR2-mediated PI3K-AKT pathway to improve renal injury in DKD, that provided a theoretical basis for PF treatment in DKD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier GmbH.)

Necroptosis was elevated in both tubulointerstitial and glomerular renal tissue in patients with diabetic kidney disease (DKD), and was most pronounced on glomerulus in the stage with macroalbuminuria. This study further explored whether paeoniflorin (PF) could affect podocyte necroptosis to protect kidney injure in vivo and in vitro . Our study firstly verified that there are obvious necroptosis-related changes in the glomeruli of DKD through bioinformatics analysis combined with clinicopathological data. STZ-induced mouse diabetes model and high-glucose induced podocyte injury model were used to evaluate the renoprotection, podocyte injury protection and necroptosis regulation of PF in DKD. Subsequently, the target protein-TNFR1 that PF acted on podocytes was found by computer target prediction, and then molecular docking and Surface plasmon resonance (SPR) experiments were performed to verify that PF had the ability to directly bind to TNFR1 protein. Finally, knockdown of TNFR1 on podocytes in vitro verified that PF mainly regulated the programmed necrosis of podocytes induced by high glucose through TNFR1. In conclusion, PF can directly bind and promote the degradation of TNFR1 in podocytes and then regulate the RIPK1/RIPK3 signaling pathway to affect necroptosis, thus preventing podocyte injury in DKD. Thus, TNFR1 may be used as a new potential target to treat DKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Jiang, Huang, Zeng, Zhu, Qi and Wu.)

Aims/Introduction: Diabetic nephropathy (DN) is one of the main complications of diabetes. Genomics may reveal the essential pathogenesis of DN. We analyzed datasets to search for key genes to explore pathological mechanisms of DN. Materials and Methods: In this study, weighted gene co-expression network analysis (WGCNA) was used to divide the differential expression genes (DEGs) from GSE142025 into different modules, and enrichment pathway analysis was conducted for each module to find key genes related to cell death pathway. Then, verification was carried out through network and histopathology. Finally, the regulatory mechanisms of key gene expression, including transcription factors (TFs), miRNA and E3 ligases related to ubiquitination, were predicted through website prediction and then miRNA results were validated using GSE51674 dataset. Results: The results of WGCNA and enrichment pathway analysis indicated that ferroptosis had significantly occurred in advanced DN (AND) group. Analysis of DEGs indicated that the occurrence and development of ferroptosis are mainly through ALOX15-mediated lipid metabolism pathway, which was found in all intrinsic cells of the glomerulus detected by IHC and IF staining. Moreover, network predictions were used for searching ALOX15-related TFs and ubiquitination. Meanwhile, the network predictions combining with other dataset furtherly discovered miRNAs which regulated ALOX15 expression. This study showed that the levels of mmu-miR-142-3p increased in DN mice kidney tissues, compared with the NC group. Conclusion: Ferroptosis existed in glomerular intrinsic cells of ADN group and its potential key candidate gene was ALOX15 which may be regulated by miR-142 and miRNA-650, TFs (CREBBP, EP300, HDAC1, MTA1, SPI1, STAT6) and E3 ligases related to ubiquitination (PML, ZMIZ1, MARCHF1, MARCHF3, MARCHF8, MARCHF11)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Jiang, Liu, Huang, Zhu, Zeng, Gao, Ma, Zhang, Zhu and Wu.)

The role of N 6 -methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterized the role of N 6 -adenosine-methyltransferase-like 3 (METTL3), whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor-α (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)-induced renal dysfunction, injury, and inflammation. Moreover, TAB3 [TGF-β-activated kinase 1 (MAP3K7) binding protein 3] was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 (insulin-like growth factor 2 binding protein 2) to its m6A-modified stop codon regions. The proinflammatory effects of TAB3 were then explored both in vitro and in vivo. Adeno-associated virus 9 (AAV9)-mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and ischemia/reperfusion-induced renal injury and inflammation than S -adenosyl-l-homocysteine, a previously identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modifications of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both genetic and pharmacological inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI.

Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN., (© 2020 The Author(s).)

Diabetes nephropathy (DN) is characterized by abnormal interactions between kidney-infiltrating macrophages and glomerular mesangial cells. Recently, a novel cell-cell communication mediated by exosomes has gained attention. Exosomes are membrane-bound vesicles that contain a variety of molecules such as proteins, lipids, DNA, mRNA, and microRNAs. Exosomes play an important role in the pathogenesis of DN. In this study, we show that high glucose (HG) led to increased excretion of exosomes from macrophages. Mesangial cells took up exosomes in vitro , which resulted in the activation and proliferation of mesangial cells and the secretion of extracellular matrix and inflammatory cytokines. In addition, C57BL/6 mice injected with exosomes from HG-treated macrophages showed morphologic and functional changes. We then showed that exosomes from HG-treated TGF-β1 knockdown macrophages induced less extracellular matrix and fewer inflammatory factors in mesangial cells compared with vector control. Our findings suggest that TGF-β1 mRNA in exosomes serves a role between macrophages and mesangial cells by activating the TGF-β1/ mothers against decapentaplegic homolog 3 pathway.-Zhu, Q.-J., Zhu, M., Xu, M.-X., Meng, X.-M., Wu, Y.-G. Exosomes from high glucose-treated macrophages activate glomerular mesangial cells via TGF-β1/Smad3 pathway in vivo and in vitro .

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

MLKL is a central mediator for necroptosis. Its knockout significantly relieves acute kidney injury (AKI). However, its upstream regulatory mechanism in AKI has not been fully elucidated. We recently reviewed how microRNAs (miRNAs), a type of well-studied epigenetic regulator, play critical roles in AKI. Here, we evaluated miRNAs that potentially target MLKL and evaluated their function in human tubular epithelial cells in response to toxic and ischemic insults. TargetScan analysis showed that miR-194-5P, miR-338-3P, miR-500a-3P, and miR-577 had MLKL binding sites. Although all 4 miRNAs are reduced in AKI, our data show that only hsa-miR-500a-3P was significantly suppressed in cisplatin-treated human tubular epithelial (HK2) cells. We further found that hsa-miR-500a-3P alleviated cisplatin-induced HK2 cell death, which was confirmed by transmission electron microscopy and flow cytometry. In addition, overexpression of hsa-miR-500a-3P decreased kidney injury molecule-1 mRNA and protein levels. Real-time PCR, ELISA, and immunofluorescence data show that hsa-miR-500a-3P protected against inflammatory response, evidenced by decreased monocyte chemotactic protein-1 and proinflammatory cytokines TNF-α and IL-8. Further, hsa-miR-500a-3P attenuated P65 NF-κB phosphorylation and promoter activity. Mechanistically, luciferase reporter assay showed that hsa-miR-500a-3P bound the 3'UTR of MLKL, thereby suppressing phosphorylation and membrane translocation of MLKL. In agreement with these findings, we identified that overexpression of hsa-miR-500a-3P attenuated cell injury and the inflammatory response in response to sodium azide treatment in an in vitro model. Results show that circulating exosomes from patients with AKI down-regulated miR-500a-3P, which suppressed cell injury and inflammation in HK2 cells. hsa-miR-500a-3P alleviated toxic and ischemic insults that were triggered by cell necroptosis and the inflammatory response in human HK2 cells by targeting MLKL. This may serve as a novel therapeutic target for treatment of AKI.-Jiang, L., Liu, X.-Q., Ma, Q., Yang, Q., Gao, L., Li, H.-D., Wang, J.-N., Wei, B., Wen, J., Li, J., Wu, Y.-G., Meng, X.-M. hsa-miR-500a-3P alleviates kidney injury by targeting MLKL-mediated necroptosis in renal epithelial cells.

Background and Objective: The evidence regarding the association between serum/plasma vitamin D (VitD) concentrations and systemic lupus erythematosus (SLE) is inconsistent. The study was based on relevant results from literatures that were identified and evaluated. The aim of this meta-analysis is to determine circulating VitD in SLE patients and explore influencing factors., Methods: Studies examining VitD levels in SLE patients were identified through targeted searches in the PubMed and EMBASE databases (up to December 2017). Data extracted from eligible studies was synthesized to calculate the standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI). A fixed or a random effects model was applied to calculate the pooled SMDs and ORs depending on heterogeneity across studies., Results: A total of 24 studies, including 6017 patients and 18,417 controls were included. The pooled analysis suggested that VitD levels were significantly lower in SLE patients compared with those in controls [SMD= -0.09, 95%CI= -0.12 to -0.06, P < 0.001]. When the studies were stratified by ethnicity, VitD concentrations were also significantly lower in Asian, Caucasian and African patients. When the studies were stratified by age, gender, VitD level was lower in patients than that in controls. Subgroup analyses stratified by measurement type (expect for radioimmunoassay) also demonstrated consistent results. Moreover, VitD insufficiency was more prevalent in SLE patients than healthy controls [OR=6.57, 95%CI=4.64-9.29]., Conclusion: Compared with healthy controls, SLE patients had lower concentration of VitD. Additionally, the prevalence of VitD insufficiency is more common in SLE patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)