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BMC Nephrology Jan 2021Immunoglobulin A nephropathy (IgAN) is identified as mesangial IgA deposition and is usually accompanied by other immunofluorescence deposits. The impact of...
Immunofluorescence deposits in the mesangial area and glomerular capillary loops did not affect the prognosis of immunoglobulin a nephropathy except C1q:a single-center retrospective study.
BACKGROUND
Immunoglobulin A nephropathy (IgAN) is identified as mesangial IgA deposition and is usually accompanied by other immunofluorescence deposits. The impact of immunofluorescent features in IgAN patients, however, remains unclear.
METHODS
Baseline clinicopathologic parameters and renal outcomes of 337 patients diagnosed with IgAN between January 2009 and December 2015 were analyzed. We then categorized these patients into four groups: without immunofluorescence deposits, mesangial-only, mesangial and glomerular capillary loops (GCLs), and GCLs-only. The study endpoint was end-stage kidney disease (ESKD) or a ≥ 50% decline in the estimated glomerular filtration rate (eGFR). Kaplan-Meier and Cox regression analyses were performed to calculate renal survival.
RESULTS
Of the 337 IgAN patients, women comprised 57.0%. Compared to patients with IgA deposition in the mesangial-only group, patients with IgA deposition in the mesangial +GCLs group were much heavier, and exhibited higher systolic blood pressure, lower serum IgG levels, and heavier proteinuria (all P < 0.05). Patients with IgG deposition in the mesangial +GCLs group presented with higher levels of cholesterol, heavier proteinuria than IgG deposition in the mesangial-only group (both P < 0.05). Compared with the mesangial-only group exhibiting C3 deposits, patients in the mesangial +GCLs group with C3 deposition had a higher systolic blood pressure (P = 0.028). A total of 38 patients (11.3%) continued to the study endpoint after a median follow-up time of 63.5 months (range,49.8-81.4). Kaplan-Meier analysis and Cox regression analysis showed that C1q deposition in the mesangial +GCLs group predicted a poor renal prognosis.
CONCLUSIONS
IgA and IgG deposits in the mesangial region and GCLs were associated with more unfavorable clinical and histopathologic findings in IgAN patients. C1q deposition in the mesangial region and GCLs predicted a poor renal prognosis. However, the impact of the pattern of immunofluorescence deposits on renal outcomes remains to be proven by further investigation.
Topics: Adult; Capillaries; Complement C1q; Female; Fluorescent Antibody Technique; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Kidney Glomerulus; Male; Prognosis; Retrospective Studies; Young Adult
PubMed: 33514328
DOI: 10.1186/s12882-021-02237-w -
Biomolecules Feb 2021Prostaglandin E (PGE) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its...
Prostaglandin E (PGE) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE in interleukin-1β plus forskolin-stimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE generation at a nanomolar level.
Topics: Animals; Cells, Cultured; Dinoprostone; Glomerular Mesangium; Heterocyclic Compounds; Molecular Docking Simulation; Prostaglandin Antagonists; Rats; Spectrum Analysis
PubMed: 33668480
DOI: 10.3390/biom11020275 -
Journal of Nephrology Apr 2023Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease caused by pathogenic mutations in the APOE gene. Collagen type III glomerulopathy (CG) is a... (Review)
Review
Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease caused by pathogenic mutations in the APOE gene. Collagen type III glomerulopathy (CG) is a sporadic condition in adults characterized by abnormal accumulation of type III collagen in the subendothelial space and mesangium of the glomerulus. We report the first case of both LPG and CG in a 21-year-old male. A search of the literature found no confirmed reports of these two concomitant nephropathies. The patient presented with hypertension, proteinuria, hematuria and hyperlipidemia. Renal pathology showed lipid vacuoles in the enlarged glomerular capillary loops and type III collagen in the segmental mesangial area and on the inner side of the glomerular basement membrane by electron microscopy. Whole-exome sequencing revealed a heterozygous mutation (c.127C>T; p. Arg43Cys) in exon 3 of the APOE gene, known as the APOE-Kyoto of LPG. In addition, two heterozygous COL4A4 mutations (c.4715C>T in exon 47 and c.5065 T>C in exon 48) were observed, the first one was suspected pathogenic and the other one was uncertain significant. There is no special treatment for these diseases. The patient was treated with lipid-lowering agents, renin-angiotensin-aldosterone system inhibition and tripterygium glycosides. The patient received double-filtration plasmapheresis and immunoadsorption therapy when renal function deteriorated dramatically. Immunoadsorption was beneficial for this patient.
Topics: Male; Adult; Humans; Young Adult; Collagen Type III; Kidney Diseases; Kidney; Kidney Glomerulus
PubMed: 36370330
DOI: 10.1007/s40620-022-01491-x -
Journal of Immunology (Baltimore, Md. :... Oct 2020In IgA nephropathy (IgAN), IgA immune complexes are deposited in the mesangium and drive inflammation and extracellular matrix (ECM) remodelling. The functional links...
In IgA nephropathy (IgAN), IgA immune complexes are deposited in the mesangium and drive inflammation and extracellular matrix (ECM) remodelling. The functional links between IgA deposition, inflammation, and matrix remodelling are not well characterized. We recently performed urine liquid chromatography-tandem mass spectrometry proteomics and identified multiple ECM glycoproteins whose expression and function in IgAN is unclear. None of the urine glycoproteins was regulated in IgAN transcriptomics, indicating that tissue remodelling rather than increased expression might contribute to their presence in urine. To investigate this, we examined the IgAN expression profile of metalloproteinases, enzymes involved in the remodelling of ECM proteins, and noted that the proteoglycanase ADAMTS5 was upregulated in IgAN kidneys. ADAMTS5 accumulated in areas of inflammation, and ADAMTS5 cells were seen in the tubulointerstitium and glomeruli. The enzyme was expressed by CD64 cells and its expression was increased by IL-1 and LPS. Analysis of myeloid cell transcriptomics revealed that ADAMTS5 is enriched in human classical monocytes. ADAMTS5 cells were present in areas of matrix remodelling and associated with ECM proteins lumican, versican, and collagen-4. Liquid chromatography-tandem mass spectrometry proteomics of kidney explants digested with ADAMTS5, identified multiple kidney proteins affected by ADAMTS5 and revealed specific proteolysis of complement C3 and fibronectin associated with IgA on immune complexes. ADAMTS5 processing of immune complex proteins reduced binding to cultured mesangial cells. ADAMTS5 is associated with interstitial inflammatory cells in IgAN and other kidney lesions and fragments relevant extracellular proteins. The proteolytic enzyme might be a new translational target relevant to inflammation and scarring in kidney disease.
Topics: ADAMTS5 Protein; Adult; Aged; Extracellular Matrix; Female; Gene Expression Regulation, Enzymologic; Glomerulonephritis, IGA; Humans; Inflammation; Kidney Glomerulus; Male; Middle Aged; Monocytes
PubMed: 32917786
DOI: 10.4049/jimmunol.2000448 -
BMJ Open Diabetes Research & Care Dec 2020The NLRP3 inflammasome is closely related to diabetes and atherosclerosis. Recent studies suggest NIMA-related kinase 7 (NEK7) is necessary for NLRP3 inflammasome...
INTRODUCTION
The NLRP3 inflammasome is closely related to diabetes and atherosclerosis. Recent studies suggest NIMA-related kinase 7 (NEK7) is necessary for NLRP3 inflammasome activation during potassium efflux. However, the expression of the NEK7/NLRP3 inflammasome pathway in diabetic lower extremity arterial disease (DLEAD) is unclear. The present study aimed to explore whether the NEK7/NLRP3 inflammasome pathway is involved in the pathogenesis of DLEAD.
RESEARCH DESIGN AND METHODS
The serum levels of interleukin-1β (IL-1β) and IL-18 in the control group (n=39), diabetes without lower extremity artery diseases group (n=39) and DLEAD group (n=85) were measured. H&E and Von Kossa staining were used to observe the vasculature of amputated feet from patients with diabetic foot. Furthermore, immunohistochemical staining, immunofluorescence and western blot were used to detect the expression of NEK7 and the NLRP3 inflammasome.
RESULTS
The serum IL-1β level in the DLEAD group was significantly increased compared with that in the control group and diabetes without lower extremity artery disease group. The serum IL-18 level was significantly higher in the DLEAD group and diabetes without lower extremity artery disease group than in the control group. H&E staining showed that the subintimal tissue of the arteries of patients with diabetic foot were highly thickened and exhibited irregular atherosclerotic plaques, and the arterial lumen was nearly occluded. Von Kossa staining showed dense brown-black calcium salt deposits in the vascular mesangium. Moreover, the expression of NEK7 and the NLRP3 inflammasome was significantly increased in the vascular cells of patients with diabetic foot, especially in vascular smooth muscle cells.
CONCLUSION
The NEK7/NLRP3 inflammasome pathway might be involved in the pathogenesis of DLEAD.
Topics: Diabetes Complications; Diabetes Mellitus; Humans; Inflammasomes; Lower Extremity; NIMA-Related Kinases; NLR Family, Pyrin Domain-Containing 3 Protein; Peripheral Arterial Disease
PubMed: 33323459
DOI: 10.1136/bmjdrc-2020-001808 -
Kidney International Reports Nov 2019Routine C4d staining in renal transplantation has stimulated its use in kidney biopsies with glomerulonephritis (GN). Methodical description on staining patterns in the...
INTRODUCTION
Routine C4d staining in renal transplantation has stimulated its use in kidney biopsies with glomerulonephritis (GN). Methodical description on staining patterns in the native kidney is not available.
METHODS
We retrospectively evaluated C4d staining in formalin-fixed paraffin-embedded sections from 519 native kidney biopsies (bx) with and without glomerular disease.
RESULTS
Strong C4d staining was consistently present in immune-complex GN, including lupus nephritis (LN) ( = 68), membranous GN ( = 24), membranoproliferative glomerulonephritis (MPGN) pattern ( = 22), fibrillary GN ( = 3), and proliferative GN with monoclonal IgG ( = 3). C4d stained all cases of postinfectious GN ( = 7) amyloidosis ( = 20) and C1q GN ( = 3). In contrast, IgA nephropathy (IgAN) ( = 34), was negative in 62% of bx, with the rest staining variably. The E1 Oxford classification score correlated with capillary wall C4d staining ( = 0.05). C4d marked the glomerular and arteriolar lesions in thrombotic microangiopathy (TMA; = 16), the glomerular sclerotic segments in focal segmental glomerulosclerosis (FSGS; = 77), and marked areas of necrosis in crescentic GN ( = 21). In diabetic glomerulopathy ( = 70), C4d marked advanced insudative lesions but was negative otherwise. C4d weakly stained the mesangium, or was negative in normal biopsies ( = 13), minimal change disease (MCD; = 21), thin basement membrane disease ( = 20), Alport ( = 3), IgM nephropathy ( = 2), C3 glomerulopathy ( = 5), acute interstitial nephritis ( = 12), acute tubular necrosis ( = 22), ischemic glomerulopathy/nephrosclerosis ( = 23), and other miscellaneous processes ( = 14). Staining in tubular basement membranes and peritubular capillaries was most common in lupus.
CONCLUSION
Based on reliable staining in lupus and membranous GN, C4d staining is potentially useful as a screening and diagnostic tool, if only paraffin-embedded tissue is available. Knowledge of C4d staining patterns in normal and pathological tissues enhances its diagnostic value.
PubMed: 31890997
DOI: 10.1016/j.ekir.2019.07.015 -
PloS One 2021Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high...
Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09-9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve.
Topics: Adult; Complement C4b; Female; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Male; Middle Aged; Prognosis; Proportional Hazards Models; Proteinuria; Renal Insufficiency; Retrospective Studies; Risk Factors; Severity of Illness Index; Thailand; Young Adult
PubMed: 34081719
DOI: 10.1371/journal.pone.0252638 -
Biomedicine & Pharmacotherapy =... Aug 2020Ergosterol (ERG) was reported to exhibit anti-inflammatory and anti-oxidative activities. Besides, ERG was found to attenuate kidney injury in the diabetic mouse....
Ergosterol (ERG) was reported to exhibit anti-inflammatory and anti-oxidative activities. Besides, ERG was found to attenuate kidney injury in the diabetic mouse. However, the protective effect of ERG in diabetic nephropathy-induced inflammation remains unclear. We aimed to study whether ERG could alleviate diabetic nephropathy-induced inflammation and explore the underlying mechanisms. The diabetic nephropathy mice model was induced by intraperitoneal injection of 30 mg/kg Streptozotocin (STZ). The inflammatory cytokines levels, and insulin concentration in the serum of both diabetic nephropathy patients and mouse model were determined by ELISA. mRNA and protein expression were analyzed by RT-PCR and Western blot, respectively. Fasting blood glucose levels were detected using a commercial kit. Blood biochemistry levels were determined by an automatic analyzer. Mesangium proliferation was detected by PAS staining. It was found that serum levels of IL-6, TNF-α, and MCP-1 dramatically increased in the diabetic nephropathy patients. In mice, ERG treatment greatly decreased fasting blood glucose levels, inflammatory cytokine levels, and renal injury, while it enhanced the insulin level. Mechanically, ERG treatment dramatically decreased NF-κB signaling pathway. Our findings highlight the potential of ERG as an effective agent to treat diabetic nephropathy.
Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Blood Glucose; Case-Control Studies; Cytokines; Diabetic Nephropathies; Disease Models, Animal; Ergosterol; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Kidney; Mice; Nephritis; Streptozocin
PubMed: 32446112
DOI: 10.1016/j.biopha.2020.110252 -
Biomedicines Aug 2021Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high...
Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients' serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic and mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.
PubMed: 34572299
DOI: 10.3390/biomedicines9091112 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Nov 2022To investigate the interventional effects of a new SUR2B/Kir6.1-type K Channel opener iptakalim on injury renal cells (the renal glomerular endothelial, mesangial and...
To investigate the interventional effects of a new SUR2B/Kir6.1-type K Channel opener iptakalim on injury renal cells (the renal glomerular endothelial, mesangial and tubular epithelial cells) and its mechanisms. ①Experimental protocol: control: the cells were treated with with 0 mg/L uric acid for 24 h; model: the cells were treated with with 1 200 mg/L uric acid for 24 h; pretreatment with iptakalim: the cells were pretreated with 0.01,0.1,1,10,100 μmol/L iptakalim for 24 h prior to treatment with 1 200 mg/L uric acid for 24 h; pretreatment with glibenclamide: the cells were preincubated with/without 10 μmol/L glibenclamide for 1 h and then treated with 10 μmol/L iptakalim for 24 h followed by incubation with 1 200 mg/L uric acid for another 24 h. ②The cell viability was measured by MTT assay and flow cytometry; the protein expressions of Kir6.1 and SUR2B and nuclear translocation were detected by immunostaining; the protein expressions of Kir6.1 and SUR2B were determined by Western blot analysis; adhesion of mononuclear cells to endothelial cells were tested by fluorimetric assay; the content of MCP-1 was measured by enzyme linked-immunosorbent assay (ELISA). The renal glomerular endothelial, mesangial and tubular epithelial cells were exposed to 1 200 mg/L uric acid for 24 h. Compared with the control group, 1 200 mg/L uric acid decreased the cell survival rates significantly (<0.01, <0.01, <0.01). Compared with the model group, pretreatment with 0.1, 1, 10, 100 μmol/L iptakalim could remarkably alleviate cellular damages of glomerular endothelium, mesangium cells induced by uric acid (<0.05, <0.01, <0.01, <0.01). The K channel blocker could clearly reduce survival rates of the renal glomerular endothelial, mesangial cells(<0.01) and markedly reverse the inhibitory effects of iptakalim on cell death (<0.05, <0.01), no obvious difference in comparison with the model group (>0.05). Compared with the model group, pretreatment with 10, 100 μmol/L iptakalim could notably attenuate cellular damages of tubular epithelial cells induced by uric acid (<0.05, <0.05). The K channel blocker could obviously damage the tubular epithelial cells (<0.01), no obvious difference in comparison with the model group (>0.05). Compared with control group, exposure of renal tubular epithelial, mesangial and glomerular endothelial cells to 1 200 mg/L uric acid for 24 h caused a significant increase in the protein expressions of Kir6.1 and SUR2B(<0.05). Compared with the model group, the overexpressions of Kir6.1 and SUR2B were suppressed in presence of iptakalim at a concentration of 10 μmol/L (<0.05). These decreases in the expressions of Kir6.1 and SUR2B were prevented by the K channel blocker, no obvious difference in comparison with the model group (>0.05). Compare with the control group, monocytic adhesion to renal glomerular endothelial cells was notably promoted by 1 200 mg/L uric acid for 24 h (<0.01). Pretreatment with 10 μmol/L iptakalim for 24 h significantly reduced the monocytic adhesion in comparison with the model group (<0.05). It was showed that the inhibitory effects of iptakalim were antagonized by the K channel blocker, no obvious difference in comparison with the model group (>0.05). After stimulating glomerular endothelial cells with 1 200 mg/L uric acid for 24 hours, the secretion of MCP-1 was significantly increased compared to the control group (<0.05). Compare with the model group, preincubation with 10 μmol/L iptakalim significantly decreased MCP-1 production (<0.05). K channel blocker suppressed the downregulation of MCP-1 protein synthesis induced by iptakalim. After stimulation with uric acid, translocation of NF-κB from cytoplasms to nuclei of renal glomerular endothelial cells were observed, while that of NF-κB was suppressed in presence of iptakalim at the concentration of 10 μmol/L. This inhibition of NF-κB translocation was clearly prevented by K channel blocker. These results suggests that a new SUR2B/Kir6.1-type K channel opener iptakalim plays interventional roles in renal cells damages caused by uirc acid and its mechanism is involved in activating Kchannels .
Topics: Endothelial Cells; Glyburide; NF-kappa B; Uric Acid; Adenosine Triphosphate
PubMed: 37308403
DOI: 10.12047/j.cjap.6356.2022.110