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Background Mild cognitive impairment (MCI) and dementia are more prevalent in patients undergoing haemodialysis (HD). Although the cerebrospinal fluid amyloid beta (Aβ) and tau (τ) have proven to be valid biomarkers for the diagnosis of Alzheimer's disease (AD) in the general population, the roles of plasma Aβ and τ for the diagnosis of cognitive impairment in HD patients remain unknown. Methods We conducted a cross-sectional study including patients receiving HD in three hospitals in Shanghai. All patients completed the Montreal Cognitive Assessment–Basic (MoCA-B). To validate the effectiveness of the MoCA-B score for screening MCI, a subset group underwent neuropsychological batteries. Serum proteomes were compared in HD patients with normal cognitive function and dementia. Plasma Aβ42, Aβ40 and total τ were measured using a single molecule array. Results A total of 311 HD patients were enrolled (mean age 63 years, 55% male). The best cut-off score of MoCA-B for differentiating MCI and normal cognition was 24, with an area under the curve of 0.94. Serum proteomics revealed that neurodegenerative pathways related to AD were enriched in HD patients with dementia. The plasma Aβ42:Aβ40 ratio was significantly reduced in patients with MCI and dementia and was independently associated with cognitive function after adjusting for age, sex and education levels. Conclusions We validated the MoCA-B as an optimal cognitive function screening instrument for MCI in HD patients. The plasma Aβ42:Aβ40 ratio was a potential biomarker in distinguishing normal cognition, MCI and dementia in HD populations. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) signaling has been reported to play a vital role in the pathogenesis of rheumatoid arthritis (RA). In current study, we sought to observe whether the active immunization induced by the mimotope could recognize EGFR, inhibit their signaling and disrupt the pathogenic behavior of fibroblast-like synoviocytes (FLS) from RA patients. We prepared a linked EGFR mimotope and performed series of experiments to detect whether the mimotope could induce the desired immune responses. To our surprises, we detected the expression of EGFR variant III (EGFRvIII), but not EGFR in the synovial tissues and FLS from patients with aggressive RA by the linked EGFR mimotope-induced antibodies (LEMIA). Meanwhile, LEMIA could inhibit the signaling caused by the autophosphorylation of EGFRvIII in the FLS. The proliferation, migration, invasion and anti-apoptosis capabilities of the EGFRvIII-expressed FLS were disrupted by LEMIA. These results suggest that EGFRvIII signaling may participate in the malignant behaviors of FLS from aggressive RA. Meanwhile, the linked EGFR mimotope could be used to detect the expression of EGFRvIII and developed to be a potential therapy agent against the aggressive FLS. [ABSTRACT FROM AUTHOR]

Research has indicated that endoplasmic reticulum (ER) stress in endothelial cells affects vascular pathologies and induces cellular dysfunction and apoptosis. Angiopoietin1 (Angpt1) has been shown to have therapeutic potential in some vascular diseases, including chronic kidney disease. This study showed that Angpt1 is a powerful factor that attenuated ER stress-induced cellular dysfunction and apoptosis in glomerular endothelial cells (GEnCs). Furthermore, Angpt1 significantly decreased the angiotensin II (Ang II)-induced expression of the ER stress response proteins GRP78, GRP94, p-PERK and CHOP. These results suggest that the Angpt1-mediated cellular protection may occur downstream of the ER stress response. In addition, both specific inhibitors and siRNAs for Tie2 reversed these changes, implying the importance of Tie2 receptor activation in the signalling pathways that prevent ER stress. The protective effects of Angpt1 are related to the activation of two downstream signalling pathways, ERK1/2 and p38 MAPK. The inhibition of these pathways with specific inhibitors, PD98059 and SB203580, respectively, partially increased the expression of chaperones that assist in folding proteins in the ER and reduce the protective effects of Angpt1. In conclusion, Angpt1 attenuated ER stress-induced cellular dysfunction and apoptosis via the Tie2 receptor/ERK1/2-p38 MAPK pathways in GEnCs. This study may provide insights into a novel underlying mechanism and a strategy for alleviating ER stress-induced injury. [ABSTRACT FROM AUTHOR]

Glycated albumin (GA), an Amadori product used as a marker of hyperglycemia and the early-stage glycation products compared to AGEs, might further promote kidney lesions in diabetic nephropathy (DN). However, the mechanisms how GA cause proximal tubular cells damage remain poorly understood. In this study, we investigated the effects of GA on fibrosis and apoptosis of renal proximal tubular cells (NRK-52E) in vitro experiments. Our results showed that GA promoted α-SMA, fibronectin (FN) and TGF-β expressions in NRK-52E cells. GA also increased cell apoptosis and stimulated the expressions of pro-caspase 3/cleaved-caspase 3. GA overloading enhanced the phosphorylation of MAPK pathway. GA-induced α-SMA, FN, TGF-β and caspase 3 expressions were completely suppressed by the NADPH oxidase inhibitor apocynin (Apo), the reactive oxygen species (ROS) scavenger N -acetylcysteine (NAC) and the latent antioxidant Astragaloside IV (AS-IV). Real-time PCR showed that GA increased Nox1, Nox2 and Nox4 mRNA expressions, especially the Nox4 expression. Furthermore, Nox4 siRNA blocked GA-induced tubular damages and the MAPK pathway activation. These results demonstrate that GA increases the permissiveness of proximal tubular cells to fibrosis and apoptosis in vitro by triggering a pathway that involves NADPH oxidase/Nox4-MAPK signaling pathway. This event may represent a key cellular effect in increasing the susceptibility of tubular cells to fibrosis and apoptosis when the tubules cope with a high GA load. This effect is instrumental to renal damage and disease progression in patients with DN. [ABSTRACT FROM AUTHOR]

Objective: To identify novel potential biomarkers and evaluate combined biomarkers for diagnosing kidney injury with considerable accuracy in preeclampsia. Methods: The level of serum and urine neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), retinol-binding protein (RBP) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assay. Results: The level of serum cystatin C, urine RBP, urine NGAL and urine KIM-1 in preeclampsia group were higher than that in the normal pregnancy group. When four biomarkers are combined, the sensitivity and specificity are 100%/98.20%. Conclusion: Urine KIM-1 is the most potential biomarker for renal injury in preeclampsia. The more biomarkers combined, the more sensitivity and specificity were increased. [ABSTRACT FROM AUTHOR]

Primary Sjögren's syndrome (pSS) is a prototypic autoimmune disease characterized by immune injury to the salivary and lacrimal glands with other systemic manifestations. Recent studies showed the adaptive autoimmune responses induced by muscarinic acetylcholine 3 receptor (M3R) contribute to the dysfunction of exocrine glands in the pathogenesis of pSS. Although the M3R-induced mononuclear cells infiltration are observed in exocrine glands in pSS patients and animal models, the role of M3R in lymphatic vessels formation has not been explored. In current study, we found the expression of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) increased in intestine of the M3R immunized mice and epidermal growth factor receptor (EGFR) mimotope could inhibit this behavior. Our results suggested that the M3R/EGFR transactivation signaling may help mononuclear cells infiltrate in exocrine glands by promoting lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Background Sarcopenia is a clinical condition that is common in patients with chronic kidney disease (CKD), especially in those on dialysis. However, the relatively complicated diagnostic procedure limits its use in clinical situations. In this study we aimed to establish a simplified tool for the diagnosis of sarcopenia in patients on hemodialysis (HD). Methods Overall, 757 eligible patients from seven HD centers in Shanghai and Suzhou, China, were recruited from 2020 to 2021. The cross-sectional data were analyzed. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Among them, 511 consecutive patients (77 with and 434 without sarcopenia) from five centers were included in the training set for the establishment of a diagnostic nomogram. Ten investigative parameters including clinical characteristics, body measurements and physical performance were used to derive the diagnostic nomogram. A total of 246 consecutive patients (47 with and 199 without sarcopenia) were included for validation of the diagnostic model. Results The average age of the enrolled patients was 60.4 ± 12.1 years, 59.8% were males and 90.5% received dialysis using an arteriovenous fistula. Overall, the sarcopenia rate was 16.4%. The training and validation sets showed no significant differences in sarcopenia rate (15.1% and 19.1%, respectively; P  = .160). The nomogram derived from the training set for sarcopenia, which was based on only four features—age, sex, body weight and grip strength—achieved high C-indexes of 0.929 [95% confidence interval (CI) 0.904–0.953] and 0.955 (95% CI 0.931–0.979) in the training and external sets, respectively, and had a well-fitted calibration curve. The cut-off value was 0.725, with a sensitivity of 0.909 and a specificity of 0.816. The nomogram accurately diagnosed sarcopenia with fewer variables and more simplified diagnostic procedures. Conclusions The nomogram had a good diagnostic capability for sarcopenia in patients on HD and may be a convenient tool for clinical use. [ABSTRACT FROM AUTHOR]

Purpose: Unconjugated bilirubin is one of the most endogenous antioxidant substances. Mildly elevated total bilirubin concentrations may protect against cardiovascular disease and total death. However, most studies only focused on the association between serum total bilirubin and the risk of cardiovascular disease and total death. This study aimed to investigate the relationship between serum indirect bilirubin (IBIL) and the cardiovascular events in maintenance hemodialysis patients. Patients and Methods: : This retrospective cohort study included 284 maintenance hemodialysis patients. Patients were divided into two groups according to the median IBIL level: high IBIL group (IBIL ≥ 3.0 μmol/L) and low IBIL group (IBIL < 3.0 μmol/L). All demographic and laboratory data were recorded at baseline. The endpoint was cardiovascular events and all-cause mortality. Results: During the median follow-up time of 62 months, 96 patients developed cardiovascular disease. There were 134 deaths. In Kaplan–Meier analysis curves, the risk of cardiovascular events in the low IBIL group was significantly higher than high IBIL group (P < 0.001). In multivariate Cox regression analysis, the risk of cardiovascular events in high IBIL group was 0.484 times (95% CI 0.278– 0.844, P = 0.010) the risk in low IBIL group. However, there was no significant association between serum IBIL level and all-cause mortality (P = 0.269). Conclusion: Our findings suggest that lower circulating IBIL levels were associated with the increased risk of cardiovascular events in maintenance hemodialysis patients. [ABSTRACT FROM AUTHOR]

Aim: We aimed to explore the detailed molecular mechanism of immune‐associated genes in membranous nephropathy (MN). Methods: A microarray data set (GSE133288) was retrieved from the Gene Expression Omnibus database. Differentially expressed mRNAs (DEMs) in MN vs control groups were identified, and MN‐related DEMs (MN‐DEMs) were further verified and screened using the comparative toxicogenomics database (CTD) database. The publicly available database, InnateDB was used to investigate immune genes, and the overlapped genes between MN‐DEMs and the immune genes were considered as MN‐related immune genes (iDEMs). A protein‐protein interaction network (PPI) was constructed based on these iDEMs, followed by function and pathway enrichment analysis. Finally, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) associated with iDEMs were predicted, followed by a lncRNA‐miRNA‐mRNA (competing endogenous RNAs, ceRNA) network construction. Results: A total of 327 DEMs and 48 iDEMs were revealed; a PPI network was constructed with 100 PPI pairs and 37 iDEMs. iDEMs including JUN and FOS were mainly enriched in pathways such as osteoclast differentiation and function including response to immobilization stress, respectively. Based on mRNA‐associated miRNA and lncRNA prediction, 30 ceRNA interactions including KCNQ1OT1‐miR‐204‐5p‐SRY‐Box Transcription Factor 4 (SOX4) were explored. Conclusion: mRNAs including FOS and JUN might participate in MN development via response to immobilization stress function and the osteoclast differentiation pathway. The mRNA SOX4 might contribute to MN progression via sponging KCNQ1OT1‐miR‐204‐5p interaction. SUMMARY AT A GLANCE: The authors investigated differentially expressed mRNA's in membranous nephropathy (MN) vs controls from a microarray data set, and identified that mRNAs including FOS and JUN might participate in MN development with SOX4 potentially contributing to MN progression. These findings assist with better understanding the molecular processes underpinning MN especially pertaining to the involvement of immune‐associated gene expression. [ABSTRACT FROM AUTHOR]

Macrophages have been recognized as a vital factor that can promote renal fibrosis. Previously we reported that the EGFR mimotope could alleviate the macrophage infiltration in the Sjögren's syndrome-like animal model. In current study, we sought to observe whether the active immunization induced by the EGFR mimotope could ameliorate renal fibrosis in the murine Unilateral Ureteral Obstruction (UUO) model. A series of experiments showed the EGFR mimotope immunization could ameliorate renal fibrosis, reduce the expressions of fibronectin, α-SMA and collagen I and alleviate the infiltrations of F4/80+ macrophages in UUO model. Meanwhile, the EGFR mimotope immunization could inhibit the EGFR downstream signaling. Additionally, the frequency of and F4/80+CD9+/FAS+ macrophages significantly increased in spleen after the EGFR mimotope immunization. These evidence suggested that the EGFR mimotope could alleviate renal fibrosis by both inhibiting EGFR signaling and promoting macrophages apoptosis. • The EGFR mimotope can ameliorate renal fibrosis in the animal model. • The EGFR mimotope can reduce the macrophages in the kidney and spleen. • The EGFR mimotope can up-regulate CD9 and FAS in the macrophages. [ABSTRACT FROM AUTHOR]

The mechanisms of proteinuria development in preeclampsia (PE) are still enigmatic. Renin–angiotensin system (RAS) components may play a role. Maternal serum and urinary concentrations of angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II), and angiotensinogen in women with PE (n = 14), gestational hypertension (n = 14), and normal pregnancy were quantified. The alteration in these concentrations was used to evaluate their relationships with podocyturia and proteinuria in PE. In addition, the podocytes cultured in vitro were interfered in serum of preeclamptic and normotensive pregnant women, with or without Ang-(1-7). The morphologic change in podocyte was observed using a microscope. The changes in podocyte-specific proteins (nephrin, CD2-associated protein [CD2AP]), the cytoskeletal protein F-actin, the tight junction protein (ZO-1), and Mas receptor (MasR) were examined by immunofluorescence. Western blot was used to examine the expression and variation of MasR. We found that the concentrations of RAS components were associated with prepartal urinary podocyte number, random urine albumin/creatinine ratio, blood pressure, and renal function. The expression of nephrin, F-actin, ZO-1, and MasR on podocytes interfered in serum of PE was significantly decreased compared to normal control and normal pregnant serum group in vitro, yet their expression was significantly increased after coculture by 10−6 mol/L Ang-(1-7) and the preeclamptic serum. The expression of CD2AP had no significant difference. We concluded that decreased Ang-(1-7) and downregulated intrarenal RAS contributed to the direct podocyte injury with proteinuria in PE. [ABSTRACT FROM AUTHOR]

Aim: Our previous study demonstrated that the cystatin C-based chronic kidney disease (CKD)-EPI equation and combined by serum creatinine (CKD-EPIscr-cys) had better capability to accurately evaluate glomerular filtration rate in the CKD participants. Considering that the accuracy of estimated glomerular filtration rate (eGFR) remains less ideally, it is essential to modify the equation by including the Chinese eGFR racial factor in order to improve its performance. Methods: Two prospective cohorts were enrolled in 2 medical centers. New equations were developed in 529 participants and validated in 313 participants. Reference glomerular filtration rate (rGFR) was taken by 99mTc-DTPA renal dynamic imaging method (Gates method). The primary outcomes of this study were bias, precision (interquartile range of difference [IQR]), and accuracy (the proportion of eGFR within 30% of rGFR [P30] and root mean square error [RMSE]) of eGFR versus rGFR. Results: In a development data set, Chinese coefficients for CKD-EPIscr (C-CKD-EPIscr), CKD-EPIcys (C-CKD-EPIcys), and CKD-EPIscr-cys (C-CKD-EPIscr-cys) were 0.871, 0.879, and 0.891, respectively. In a validation data set, C-CKD-EPIcys was the most accurate with highest P30 value (62.3%), relative lowest IQR (15.45), and RMSE (0.80) among 6 equations, though the bias of C-CKD-EPIcys was not better than CKD-EPIcys. C-CKD-EPIscr and C-CKD-EPIscr-cys equations were improved in bias (p < 0.001), -precision, and accuracy (p = 0.004 and <0.001 for P30) compared with CKD-EPIscr and CKD-EPIscr-cys. Conclusion: C-CKD-EPIcys was the most accurate with the highest P30 value, relative lowest IQR, and RMSE among 6 equations. C-CKD-EPIscr and C-CKD-EPIscr-cys equations were improved in bias, precision, and accuracy. Other external validation of these equations is needed. [ABSTRACT FROM AUTHOR]

Objective. The elder diabetic patients increases rapidly in China and often accompany with hyperuricemia. Recently evidences show that renal function has been impaired in part of diabetic patients with normoalbuminuria. Therefore, we investigated the relationship between serum uric acid (SUA) and renal function in Chinese elder diabetes with normoalbuminuria. Methods. The physical examination data from 1052 cases of diabetic residents with normoalbuminuria aged 70 years and over in the Jiangchuan community of Minhang District, Shanghai, from October 2011 to September 2014 was analyzed retrospectively. Each received height, body weight, waist circumference (WC), waist-to-hip ratio (WHR), blood pressure (BP), and collected samples of fasting blood and morning urine to detect blood routine, blood glucose, glycosylated hemoglobin (HbA1c), blood lipids, serum creatinine, urinary albumin, urine creatinine, and urine PH value. Correlation between SUA and renal function, an index of which is estimated using estimated glomerular filtration rate (eGFR), was analyzed. Results. The prevalence of hyperuricemia was 21.10%. Levels of WC and triglyceride (TG) increased and the levels of HbA1c, high density lipoprotein-cholesterol (HDL-C), eGFR, and urine PH decreased while the levels of SUA increased. Moreover, negative correlation of eGFR with age, WC, leukocyte, and SUA (Pearson r=0.415) was observed via Pearson correlation analysis. It indicates the strong association between SUA and eGFR. Furthermore, eGFR independently associated with SUA, age, leukocyte, hemoglobin (Hb), and fasting blood glucose (FBG) was confirmed by multiple linear stepwise regression analysis. Conclusion. SUA may play an important role in the decrease of eGFR in elderly Chinese diabetic patients with normoalbuminuria. [ABSTRACT FROM AUTHOR]

Background/Aims: Angiotensin II type I receptor agonistic autoantibody (AT1-AA) is closely related to pre-eclampsia, which is characterized by proteinuria and hypertension. AT1-AA has been shown to enhance the effect of AngII in pre-eclampsia, such as production of endothelin-1, activation of ROS, and vasoconstriction, which are considered to be associated with hypertension; however, whether or not AT1-AA participates in podocyte damage leading to the generation of proteinuria has not been reported. In this study we investigated the role of pre-eclamptic serum AT1-AA on podocytes and the mechanism underlying the generation of proteinuria. Methods: The levels of AT1-AA isolated from pre-eclamptic sera were determined by an enzyme-linked immunosorbent assay. Human podocytes were cultured in vitro and treated with various concentrations of AT1-AA. Whether or not an ERK1/2 inhibitor and TRPC6 siRNA inhibit the effect of AT1-AA on podocytes was determined. Western blot was used to detect the expression of podocyte-specific proteins (nephrin, synaptopodin, and podocin) and the phosphorylation of ERK1/2 and TRPC6. The arrangement of F-actin was observed by immunofluorescence. A Calcineurin Cellular Activity Assay Kit was used to detect calcineurin activity. Changes in the intracellular Ca2+ concentration was determined by confocal laser. Results: AT1-AA induced a decrease in podocyte-specific protein expression and calcineurin activity and increased expression of p-ERK1/2 and TRPC6 protein and the intracellular Ca2+ concentration. Immunofluorescence revealed rearrangement of F-actin. PD98059, an inhibitor of ERK1/2, and TRPC6 siRNA attenuated the decreased expression of podocyte-specific proteins and decreased intracellular Ca2+ concentration. The expression of TRPC6 was reduced following the addition of ERK1/2 inhibitor. Conclusion: AT1-AA induced podocyte damage in a dose-dependent manner. The underlying mechanism might involve activation of the TRPC6 –calcium/calcineurin pathway. This study provides new details regarding podocyte injury and the mechanism underlying the generation of proteinuria in pre-eclampsia. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to investigate the renoprotective effect of glucagon-like peptide-1 (GLP-1) against renal tubular injury in C57BL/6 mice induced by a high-fat diet (HFD). Methods: Twenty C57BL/6 mice were fed HFD for 12 weeks. Ten of these mice were treated with GLP-1 at 200 μg/kg subcutaneously twice daily for 4 weeks (HFDG group), and the other ten mice received vehicle only (HFD group). Ten mice fed standard rodent chow served as controls (Con group). Body weight, kidney weight, food intake, and systolic blood pressure were measured. The expression of endoplasmic reticulum stress (ERS) markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis in the kidney were examined utilizing western blotting, immunohistochemistry and TUNEL, respectively. Angiotensin II and angiotensin II type 1 receptor (AT1R) were examined by ELISA. Human proximal tubule epithelial cells (HK2) were treated with GLP-1(150 nM) followed by treatment with palmitic acid (500 nM [PA]) for 24 h. HK2 cells treated with BSA were used as controls. The protein levels of ERS markers, apoptosis-associated protein, and AT1R were measured by western blotting. Results: Increase of body weight, food intake, and systolic blood pressure was less pronounced in GLP-1 treated HFDG mice compared to HFD mice. The levels of ERS markers (BIP, p-eIF2α, ATF4, and CHOP) and apoptosis decreased following GLP-1 treatment in vivo and in vitro (p<0.05). Increased AT1R induced by HFD and PA were blocked with GLP-1 treatment. In contrast, the level of angiotensin II after GLP-1 treatment was not significantly different between the HFD and HFDG mice. Conclusion: The study indicated that saturated fatty acids induced ERS and apoptosis in the kidney and increased AT1R expression. GLP-1 treatment exerted renoprotective effects against saturated fatty acid-induced kidney tubular cell ERS and apoptosis together with inhibition of AT1R expression in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Background: Currently, creatinine- or cystatin C-based glomerular filtration rate (GFR) estimation equation has been recommended to assess GFR in CKD patients. However, it is still obscure whether those equations performed consistently outstandingly in Chinese population. Methods: The equations were validated in a population totaling 632 participants (mean age 61.6 ± 12.3 years). The estimated GFR (eGFR) calculated separately by six equations (C-MDRD, C, C, CKD-EPI, CKD-EPI, and CKD-EPI equations) was compared with the reference GFR (rGFR) measured by the Tc-DTPA renal dynamic imaging method. Participants were divided into age and rGFR specific subgroups. Results: CKD-EPI equation had a larger area under receiver operating characteristic curve (ROC) and relative higher sensitivity (79.8 %) and specificity (93 %) to diagnose CKD. CKD-EPI and CKD-EPI equations appeared to be more accurate with higher proportion of eGFR within 30 % of rGFR ( P ) value. Those two equations performed as well in older people as in the younger population. The CKD-EPI equation acquired the highest P (80.9 %) in subgroups with rGFR ≥60 mL/min/1.73 m, while the CKD-EPI equation yielded the best performance in the rGFR <60 mL/min/1.73 m subgroup. Conclusion: CKD-EPI formula had better capability to accurately evaluate GFR in the participants CKD stages 1-2 in Chinese ethnic. The application of the cystatin C-based equations may be the optimal one for patients of moderately to severely injured GFR. Considering the accuracy in the entire range of participants less ideally, the additional of the Chinese racial factor is assumed to be essential. [ABSTRACT FROM AUTHOR]

Aims: Amounts of macrophages were infiltrated in glomeruli in diabetic nephropathy. Heparanase has been thought to be closely related to proteinuria. Our aims were to determine the effect of heparanase on the inflammation in AGEs-stimulated macrophages and its role on the functions of glomerular endothelial cells (GEnCs).Methods: The expression of inflammation cytokines in macrophages were assayed by q-RT PCR, western, and ELISA. Then western was used to measure the expression of RAGE and key proteins in NF-κB pathway in macrophages. The expression of the adherence molecules and tight junction proteins in GEnCs were assessed by western. The adherence of mononuclear cells to GEnCs were observed by HE staining and transendothelial FITC-BSA were tested for the permeability of GEnCs.Results: HPA siRNA and heparanase inhibitor sulodexide could attenuate the increasing inflammatory factors (TNF-α and IL-1β) in AGEs-stimulated macrophages. NF-κB inhibitor PDTC could also decrease the augmented inflammation cytokines through inhibiting the activation of the NF-κB pathway induced by AGEs. The phosphorylation of NF-κB signaling pathway could be also attenuated by HPA siRNA and sulodexide, the same to the receptor of AGEs RAGE. When the macrophage-conditioned culture medium were added to the glomerular endothelial cells, we found HPA siRNA and sulodexide groups could decrease the increasing adherence and permeability of GEnCs induced by AGEs.Conclusions: Heparanase increases the inflammation in AGEs-stimulated macrophages through activating the RAGE-NF-κB pathway. Heparanase driven inflammation from AGEs-stimulated macrophages increases the adherence of GEnCs and augments the permeability of GEnCs. [ABSTRACT FROM AUTHOR]

Aldosterone has been recognized as a risk factor for the development of chronic kidney disease (CKD). Studies have indicated that enhanced activation of epidermal growth factor receptor (EGFR) is associated with the development and progression of renal fibrosis. But if EGFR is involved in aldosterone-induced renal fibrosis is less investigated. In the present study, we examined the effect of erlotinib, an inhibitor of EGFR tyrosine kinase activity, on the progression of aldosterone-induced renal profibrotic responses in a murine model underwent uninephrectomy. Erlotinib-treated rats exhibited relieved structural lesion comparing with rats treated with aldosterone alone, as characterized by glomerular hypertrophy, mesangial cell proliferation and expansion. Also, erlotinib inhibited the expression of TGF-β, α-SMA and mesangial matrix proteins such as collagen Ⅳ and fibronectin. In cultured mesangial cells, inhibition of EGFR also abrogated aldosterone-induced expression of extracellular matrix proteins, cell proliferation and migration. We also demonstrated that aldosterone induced the phosphorylation of EGFR through generation of ROS. And the activation of EGFR resulted in the phosphorylation of ERK1/2, leading to the activation of profibrotic pathways. Taken together, we concluded that aldosterone-mediated tissue fibrosis relies on ROS induced EGFR/ERK activation, highlighting EGFR as a potential therapeutic target for modulating renal fibrosis. [ABSTRACT FROM AUTHOR]

Proteinuria is universal to all patients with preeclampsia. We examined the urinary podocytes in women with preeclampsia (n = 14), gestational hypertension (n = 14), and normal pregnancy. Maternal serum and urinary concentrations of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and the antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) were detected. These concentrations were used to evaluate the urinary excretion of podocytes and the alteration of angiogenic factors and to assess their relationships to proteinuria in preeclampsia. Our studies suggest that the urinary podocyte number and angiogenic factors are correlated with random urine albumin/creatinine ratio and blood pressure. Receiver–operating characteristic (ROC) curves of serum and urinary PlGF and the PlGF/sFlt-1 ratio as well as the presence of podocyturia confirmed their usefulness in distinguishing preeclamptic and normotensive pregnant women. In addition, combinations of serum or urinary PlGF or podocyturia tests in parallel or in series provided the best clue for identifying patients with preeclampsia. We considered that the dysregulation of angiogenic factors and its subsequent podocyte injury may contribute to the mechanism of proteinuria development in preeclampsia. [ABSTRACT FROM PUBLISHER]

Previously we identified four Tocilizumab mimotopes and antibodies induced by these mimotopes could bind to IL-6R (interleukin-6 receptor) and regulate the downstream signaling pathways. On the basis of obtained research data, we sought to investigate whether the therapeutic strategies by Tocilizumab mimotope vaccination could be effective in the renal fibrosis model and show the desired activity by inhibiting IL-6 signaling in current study. We immunized the mice with the Tocilizumab mimotope and then performed the unilateral ureteric obstruction (UUO) surgery. Masson-trichrome staining and immunohistochemistry were performed to evaluate the renal fibrosis. The activations and differentiations of F4/80+ cells in the spleens and kidneys were detected by flow cytometry, immunohistochemistry and immunofluorescence. Signaling pathways involved IL-6, pro-fibrotic and ferroptosis were analyzed by immunoblot assay. The free iron and lipid oxidation end product were performed by Prussian blue staining and immunohistochemistry. The injury and apoptosis in the kidneys were evaluated by immunofluorescence. The results showed the mimotope vaccination could reduce the level of fibrosis, injury and apoptosis by down-regulating the pro-fibrotic proteins, alleviating the activations and differentiations of macrophage F4/80+ cells in UUO models. IL-6/ERK signaling pathway was inhibited with the mimotope vaccination. The ferroptosis inhibited proteins significantly increased after the mimotope vaccination. On the contrary, the levels of free iron and lipid oxidation end product were observed to decrease in the mimotope treatment group. Our results suggested that the Tocilizumab mimotope vaccination might be an alternative therapy to against renal fibrosis. • The Tocilizumab mimotope can ameliorate renal fibrosis in the animal model. • The levels of fibrotic proteins decreased with the mimotope immunization. • The mimotope can reduce the macrophages in the kidney and spleen. • The mimotope can inhibit ERK but not STAT3 signaling. • The mimotope can inhibit ferroptosis in the kidney tissue. [ABSTRACT FROM AUTHOR]