Development Of Chronic Glomerulonephritis Research Articles

High-throughput data on circular RNA reveal novel insights into chronic glomerulonephritis.

Circular RNAs (circRNAs), a unique novel type of RNA, have been widely reported to be involved in physiologic and pathologic processes in humans. However, the exact molecular pathogenesis of circRNAs in chronic glomerulonephritis (CGN) is far from clear. This paper aims to evaluate the specific expression profile of circRNAs in renal cortex tissues from Adriamycin-induced CGN rats. CircRNAs were screened in renal cortex tissues from 3 CGN rats and 3 control rats by using high-throughput sequencing (HTS). Then, 4 circRNAs were selected randomly for verification by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, the differentially expressed (DE) circRNAs were analyzed by bioinformatics methods. In total, 31 significantly DE circRNAs were identified, which revealed their potential roles in CGN; in particular, we found that 4 confirmed altered circRNAs (rno-circ-RNAs 689, 3217, 1327, and 5001) might play important roles in the development of CGN. This study reveals a cluster of circRNAs that are DE in Adriamycin-induced CGN rats, which brings us closer to understanding the pathogenic mechanisms and may provide new potential targets for clinical treatment.

Long Non-Coding NONRATG001910.2 Promotes the Proliferation of Rat Mesangial Cell Line HBZY-1 Through the miR-339-3p/CTNNB1 Axis.

Chronic glomerulonephritis (CGN) is one of the leading causes of end-stage renal disease (ESRD). A growing body of literature emphasizes the important role of long non-coding RNAs (lncRNAs) in the development and progression of the disease. However, the function of NONRATG001910.2 in the development of CGN was not well understood. This research aimed to investigate the effect of NONRATG001910.2 on CGN and revealed its potential molecular mechanisms. In this work, the expression of NONRATG001910.2 was detected by quantitative real-time polymerase chain reaction (qRT-RCR) in cell lines. We found that NONRATG001910.2 was significantly up-regulated in lipopolysaccharide (LPS) induced cells. High NONRATG001910.2 levels were associated with the development of CGN. In addition, NONRATG001910.2 knockdown inhibited cell proliferation and cell cycle. At the same time, we found that up-regulation of microRNA-339-3p (miR-339-3p) abrogated the biological roles of NONRATG001910.2 up-regulation. Moreover, the knockdown of CTNNB1 can upregulate miR-339-3p expression, thereby inhibiting cell proliferation. In conclusion, these results demonstrated that NONRATG001910.2 in LPS-stimulated rat mesangial cell line HBZY-1 (HBZY-1) by targeting miR-339-3p, which subsequently promotes the expression of CTNNB1, and suggested that NONRATG001910.2 may be a potential biomarker.

Endothelial expression of fractalkine (CX3CL1) is induced by Toll-like receptor 3 signaling in cultured human glomerular endothelial cells

Background: Endothelial expression of membrane-bound fractalkine/CX3CL1 (Fkn) reportedly acts as a strong mediator of inflammation. Toll-like receptor 3 (TLR3) axes are thought to play some roles in the development of chronic glomerulonephritis (CGN) including lupus nephritis (LN). However, detailed mechanism of TLR3-mediated Fkn expression in glomerular endothelial cells (GECs) remains to be elucidated.Methods: We examined the effect of polyinosinic–polycytidylic acid (poly IC) on Fkn expression in cultured human GECs. Fkn mRNA and protein levels were quantified by real-time PCR and enzyme-linked immunosorbent assay, respectively. To further elucidate the effects of poly IC on this signaling pathway, we used small-interfering RNA (siRNA) to knockdown expression of TLR3, nuclear factor (NF)-κB p65, interferon (IFN)-β, and IFN regulatory factor 3 (IRF3). We then analyzed whether pretreatment of chloroquine or dexamethasone (DEX) inhibits poly IC-induced Fkn expression.Results: We found that poly IC-induced Fkn expression in GECs, and that this involved NF-κB, IFN-β, and IRF3. Pretreating cells with chloroquine, but not DEX attenuated poly IC-induced Fkn expression in GECs.Conclusion: Since the activation of TLR3/NF-κB/IFN-β/Fkn and TLR3/IRF3/Fkn axes is involved in inflammatory reactions in GECs, intervention of glomerular TLR3 signaling may be a suitable therapeutic strategy for treating CGN especially LN.

Effects of Qi Teng Xiao Zhuo granules on circRNA expression profiles in rats with chronic glomerulonephritis.

Objectives: To screen and study circular RNA (circRNA) expression profiles in QTXZG-mediated treatment of chronic glomerulonephritis (CGN) induced by adriamycin in rats and to research the possible roles and molecular mechanisms of QTXZG.Materials and methods: Next-generation RNA sequencing was used to identify circRNA expression profiles in CGN after QTXZG treatment compared with a CGN model group and a control group. Bioinformatics analysis was performed to predict potential target miRNAs and mRNAs. GO and pathway analyses for potential target mRNAs were used to explore the potential roles of differentially expressed (DE) circRNAs.Results: We identified 31 and 21 significantly DE circRNAs between the model group vs the control group and the model group vs the QTXZG group, respectively. Four circRNAs that resulted from the establishment of the CGN model were reversed following treatment with QTXZG. Further analysis revealed that these four circRNAs may play important roles in the development of CGN.Conclusions: This study elucidated the comprehensive expression profile of circRNAs in CGN rats after QTXZG treatment for the first time. Analysis of the circRNA–miRNA–mRNA–ceRNA network to determine potential function provided a comprehensive understanding of circRNAs that may be involved in the development of CGN. The current study indicated that therapeutic effects of QTXZG on CGN may be due to regulation of circRNA expression.

Effect of serum Th1/Th2 cytokine imbalance on the occurrence and development of various chronic glomerulonephritis

Objective: To explore the changes of serum interferon-γ (IFN-γ) and interleukin-10 (IL-10) of various chronic glomerulonephritis (CGN) patients and further investigate the effect of serum cytokine Th1/Th2 on the occurrence and development of various CGN. Methods: Venous blood of 9 patients with IgA mesangioproliferative glomerulonephritis (IgA nephropathy), 18 patients with non-IgA mesangioproliferative glomerulonephritis (non-IgA MsPGN), 7 patients with membranous nephropathy (MN), 6 patients with focal segmental sclerosing glomerulonephritis (FSGS), 14 patients with chronic renal failure, and 20 health people were collected for the study. Serum IFN-γ and IL-10 were assayed by double antibody sandwich ELISA, and there was a measurement of 24 h urinary protein excretion and serum creatinine which were statistically analysed. Results: The IFN-γ of the patients with IgA nephropathy or non-IgA MsPGN saw a great growth, but that of the patients with MN badly reduced, and IFN-γ of the patients’ non-IgA MsPGN was positively related to 24 h urinary protein excretion; IL-10 of the patients IgA nephropathy, non-IgA MsPGN, FSGC and CRF saw a significant decrease, and that of the patients with CRF was negatively associated with serum creatinine. Conclusion: Serum IFN-γ plays a role in the improvement of immunologic injury of mesangioproliferative glomerulonephritis which is related to the formation of proteinuria; the occurrence and development of CGN is closely linked to the decrease of IL-10, so does the development of CRF, and the imbalance of serum TH1/TH2 cytokines has certain correlation with clinical indexes.

Rare Renal Pseudotumor Associated with Chronic Glomerulonephritis Mimicking Renal Cell Carcinoma

We describe a unique case of chronic glomerulonephritis that simulated a renal neoplasm observed on abnormal imaging. Histologic examination of the resected specimen supported the assumption that the observed mass lesion resulted from regional sparing in the development of chronic glomerulonephritis. We believe this case is the first to show the etiology of pseudotumor as an extremely uncommon manifestation of chronic glomerulonephritis by histologic examination.

Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency

The activity of plasmin plays a critical role in the development of chronic glomerulonephritis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of plasmin generation. We hypothesized that TAFI is involved in the pathogenesis of glomerulonephritis because it inhibits plasmin generation. To demonstrate this hypothesis, we compared the development of immune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulonephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addition, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were significantly decreased in TAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI-knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may constitute a novel molecular target for the therapy of this disease.

Interleukin-6 gene polymorphism and faster progression to end-stage renal failure in chronic glomerulonephritis

Interleukin-6 (IL-6) is a multifunctional cytokine produced by different cell types, including monocytes, lymphocytes, endothelial and mesangial cells. Deregulated production of IL-6 was found to be involved in mesangial proliferative glomerulonephritis. We investigated whether the single nucleotide polymorphism (SNP) in the promoter region of the IL-6 gene is associated with a development of chronic glomerulonephritis (CGN). The study group consisted of 541 patients with CGN. Of those 338 already progressed to ESRD. The control group involved 253 healthy individuals. All subjects were genotyped for the -634 C/G polymorphism of the IL-6 gene by polymerase chain reaction (PCR). PCR product was digested with BsrBI restriction endonuclease and analyzed on 3% agarose. The allele and genotype frequencies were similar between CGN patients in a pre-dialysis stage and control subjects. Significantly increased frequency of the G allele was observed in the ESRD patients (13% vs. 6% in pre-dialysis stage, P < 0.01). After dividing ESRD patients according to time from reported disease onset to ESRD, those with time < or =5 years showed even higher G allele frequency (21% vs. 13% in entire ESRD group). Interestingly, most of the GG homozygotes were in this faster progressing group. Both subgroups were comparable for sex, age, BMI, total cholesterol and serum creatinine. The multivariate logistic regression analysis revealed that the IL-6 genotype with the G allele was an independent risk factor of progression to ESRD (P < 0.001). Our results indicate that the IL-6 -634 G/C polymorphism may be a possible risk factor for faster progression of chronic glomerulonephritis to ESRD. It is also possible that this polymorphism is in linkage disequilibrium with another functional polymorphism in the II-6 gene or its vicinity.

Polymorphic markers Val762Ala and Leu54Phe of the ADPRT1 gene associated with chronic glomerulonephritis in Russian patients from Moscow

A comparative analysis of allelic and genotype distribution of polymorphic markers Val762Ala and Leu54Phe of ADPRT1 gene encoding poly(ADP-ribose)polymerase I has been performed in chronic glomerulonephritis patients compared to normal controls. This has shown a significant difference in the ADPRTI gene polymorphic marker Val762Ala allelic and genotype frequency distribution between chronic glomerulonephritis patients and healthy controls (according to Fisher's exact test). At the same time the allelic and genotype frequency for a polymorphic marker Leu54Phe distribution did not show significant difference between these groups. Therefore, we have concluded that the ADPRTI gene polymorphic marker Val762Ala is associated with the development of chronic glomerulonephritis in Russian patients of the Moscow region.

Genetic variants of microsomal metabolism and susceptibility to hydrocarbon-associated glomerulonephritis.

Hydrocarbon (HC) exposure can play a role in the development of chronic glomerulonephritis (GN). Interindividual variations in various metabolizing enzymes may influence HC biotransformation, and hence susceptibility to HC-associated GN. We evaluated the role of human genotypic polymorphism in HC-associated GN, in 41 patients (30 male, 11 female) with primary GN (17 diffuse mesangial proliferative GN, 12 focal segmental GN, 11 membranous GN, one membranoproliferative GN) and 60 (46 male, 14 female) healthy controls. Genotypic polymorphisms of (CYP) P450 2D6 (CYP2D6), glutathione S-transferases mu (GSTM1) and theta (GSTT1) and N-acetyltransferase (NAT-2) were determined using polymerase chain reaction analysis of white-blood-cell DNA. HC exposure scores were determined using a validated questionnaire, and were significantly elevated in GN patients compared to controls. While no significant differences in the various genotypic frequencies were observed in the GN group overall, compared to controls, there was a significant increase in GSTM1 null (n = 10) to GSTM1 wild type (n = 1), and NAT fast (n = 10) to slow (n = 1) acetylators, in the membranous GN group compared to controls (p < 0.05). These results suggest a possible role for GSTM1 null and NAT fast acetylator in the development of HC-associated membranous GN.

Induction of Irreversible Glomerulosclerosis in the Rat by Repeated Injections of a Monoclonal Anti-Thy-1.1 Antibody

The present experiment demonstrated that an irreversible glomerulosclerosis could be induced in the rat through repeated intravenous administrations of OX-7 (a monoclonal anti-Thy-1.1 antibody). Rats were injected with 0.2 mg of affinity-purified OX-7 at 1-week intervals for a period of 4 weeks. Glomerular damage was periodically examined at light-microscopic level. Thirty-five days after the initial injection (7 days after the final injection), capillary aneurysms and expansion of the mesangial areas with hypercellularity were frequently observed. Similar glomerular damage was also observed in rats 7 days after they received a single injection of either 1.0 or 0.2 mg of OX-7. After repeated injections, 112 days from the initial administration (84 days after the final injection), approximately 60% of the glomeruli had expanded mesangial areas with an apparent increase in the mesangial matrix. The result contrasts sharply with that obtained from a single injection of OX-7 in that more than 85% of the glomeruli showed no abnormalities 84 days after the injection. This chronic model, as a result of repeated injections of the antibody, could serve as a potential for further investigation of the mechanisms involved in the development of chronic glomerulonephritis.

Complement C6 and C7 polymorphisms in Japanese patients with chronic glomerulonephritis.

C6 and C7 types were studied in 158 Japanese patients with different types of chronic glomerulonephritis: 75 patients with IgA nephropathy (IgA-N); 49 patients with idiopathic membranous nephropathy (IMN), and 34 patients with minimal-change nephrotic syndrome (MCNS). There were significant differences in the C6 and C7 allele and phenotype frequencies between the patient groups and controls. A strong association was found between IgA-N and C7 5 phenotype (p less than 0.001, RR = 12.71), and between MCNS and C7 5 phenotype (p less than 0.001, RR = 14.20). A significant association between MCNS and C6 B2 phenotype (p less than 0.05, RR = 2.42) was also found. In the IMN patient group, a significant association with C7 4 phenotype (p less than 0.05, RR = 2.42) was observed. Thus, C6 and C7 phenotypes may be causative factors in the development of chronic glomerulonephritis.

Urinary prostaglandins and thromboxane in patients with chronic glomerulonephritis.

To evaluate the potential contribution of prostaglandins (PGs) and thromboxane (TX) to the development of chronic glomerulonephritis, we measured the urinary excretion of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by radioimmunoassay in 36 patients with chronic glomerulonephritis. In patients with nephrotic syndrome, urinary excretion of PGE and TXB2 was highly increased, whereas that of PGF2 alpha and 6-keto-PGF1 alpha remained normal. In patients with non-nephrotic chronic glomerulonephritis, urinary excretion of TXB2 was significantly increased, whereas that of PGE and 6-keto-PGF1 alpha remained normal and that of PGF2 alpha was significantly decreased. In patients with chronic renal failure, the urinary excretion of all PGS and TX was markedly decreased presumably due to a decrease in the number of cells which can metabolize arachidonic acid. These results suggest that TXA2 plays an important role as an exaggerating factor in the development of chronic glomerulonephritis, particularly that accompanying nephrotic syndrome, and that renal synthesis of PGE is compensatorily increased to maintain renal function in nephrotic syndrome.

Light and Electron Microscopic Studies of Kidneys in Toxemia of Pregnancy by Means of Renal Biopsy

Light and electron microscopical examinations were performed on kidney specimens obtained from 52 cases with toxemia of pregnancy by means of needle biopsy. The main renal injuries were found in glomeruli. Glomerular lesions were initiated by precipitation of plasmal elements in lamina rara interna and followed by invasion of mesangial cells which formed membranous structures resembling lamina densa. The structures were recognized in histological sections as the characteristic reduplication of capillary basement membrane. Distinct correlation was confirmed between the intensity of glomerular involvement and proteinuria. In cases with conspicuous glomerular lesions immediately after delivery, protracted proteinuria over months was generally observed. Glomerular lesions had, however, no bearing on the development of persisting hypertension after toxemia of pregnancy. The development of chronic glomerulonephritis on the basis of toxemia of pregnancy was not confirmed. In cases with prolonged hypertension after delivery, the second biopsies revealed more or less pronounced fibroelastic hyperplasia of arteriolar intima. The lesions were regarded to belong to results, not to causes, of hypertension.