Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

Tao, Jun; Xie, Jingyuan; Ren, Hong; Liu, Jian; Zhang, Weijia; Wei, Chengguo; Xu, Jing; Zhang, Wen; Xiao, Li; Wang, Weiming; Lv, Danfeng; He, John Cijiang; Chen, Nan

doi:10.1371/journal.pone.0140453

Cited by 14 publications

(13 citation statements)

References 38 publications

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“…NEP is widely expressed in many tissues, including the nervous system, and degrades a number of substrates such as enkephalins, substance P and atrial natriuretic peptide, and, most notably, the “Alzheimer peptide,” Aβ. Moreover, MME is also abundantly expressed in the kidney, and previous studies have suggested that MME might play a role in the normal physiological function of podocytes and was involved in various renal diseases . However, renal failure and nephrotic syndrome were not observed in 8 patients evaluated, except for 2 who had mild proteinuria (Supplementary Table 3).…”

Section: Discussionmentioning

confidence: 93%

“…Moreover, MME is also abundantly expressed in the kidney, and previous studies have suggested that MME might play a role in the normal physiological function of podocytes and was involved in various renal diseases. 35,36 However, renal failure and nephrotic syndrome were not observed in 8 patients evaluated, except for 2 who had mild proteinuria ( Supplementary Table 3). These data indicated that loss-of-function mutations in the MME gene may be not sufficient to cause congenital renal disease.…”

Section: Discussionmentioning

confidence: 99%

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Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Higuchi

Hashiguchi

Yuan

et al. 2016

Annals of Neurology

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ObjectiveThe objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.MethodsTo efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging.InterpretationOur results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Higuchi

Hashiguchi

Yuan

et al. 2016

Annals of Neurology

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“…It is also reported that the TGF-β1 pathway has an important role in the pathogenesis of FSGS. [26][27][28] The reduced number of podocytes induced by apoptosis has a serious role in the development of MGN and decreased levels of miR-186 leads to an increase in its target genes Toll-like receptor 4 (TLR4), caspase-3, and P2X7 that are involved in apoptosis 21 and may contribute to the development of FSGS. A small sample size was the possible limitation of the present study.…”

Section: Dovepressmentioning

confidence: 99%

<p>Expression Levels of miR-30c and miR-186 in Adult Patients with Membranous Glomerulonephritis and Focal Segmental Glomerulosclerosis</p>

Hejazian¹,

Ardalan²,

Shoja

et al. 2020

IJNRD

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Background: Nephrotic syndrome is a common renal problem with different histopathogenesis. MicroRNAs are reported to be involved in the pathophysiology of the syndrome. The aim of this study was to study the levels of miR-30c and miR-186 in NS patients. Methods: Sixty patients with primary NS (membranous glomerulonephritis (MGN, N=30) and focal segmental glomerulosclerosis (FSGS, N=30)) and 24 healthy volunteers were included. Expression levels of the miR-30c and miR-186 were evaluated in plasma and peripheral blood mononuclear cell (PBMC) samples of adult patients with NS using real-time PCR. Moreover, an in-silico analysis was performed to understand the signaling pathways and biological procedures that may be regulated by these miRNAs. Results: In the MGN group, significantly elevated levels of miR-30c and miR-186 were observed in PBMC (P= 0.037) and plasma (P= 0.035) samples, respectively. Moreover, there was a significant increase in miR-30c levels in PBMC samples of the FSGS group when compared to healthy controls (P= 0.004). In ROC curve analysis, combined levels of the studied miRNAs could discriminate cases from controls in plasma and blood cells (AUC≥0.72, P<0.05). Conclusion: A panel of miRNAs may be potential biomarkers in plasma and PBMCs samples of NS patients with different subclasses. More investigations are needed with a large sample size to validate the diagnostic values of the reported miRNAs.

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“…Gene expression studies using kidney biopsies from patients with FSGS have been performed in order to identify gene expression signatures in patients with FSGS that can be correlated with clinical phenotypes or therapeutic response[23–26]. However, the experimental design of these studies did not allow for the specific identification of pathways activated by the sera of affected patients.…”

Section: Introductionmentioning

confidence: 99%

Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis

et al. 2019

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Focal segmental glomerulosclerosis (FSGS) accounts for about 40% of all nephrotic syndrome cases in adults. The presence of several potential circulating factors has been suggested in patients with primary FSGS and particularly in patients with recurrent disease after transplant. Irrespectively of the nature of the circulating factors, this study was aimed at identifying early glomerular/podocyte-specific pathways that are activated by the sera of patients affected by FSGS. Kidney biopsies were obtained from patients undergoing kidney transplantation due to primary FSGS. Donor kidneys were biopsied pre-reperfusion (PreR) and a subset 1–2 hours after reperfusion of the kidney (PostR). Thirty-one post reperfusion (PostR) and 36 PreR biopsy samples were analyzed by microarray and gene enrichment KEGG pathway analysis. Data were compared to those obtained from patients with incident primary FSGS enrolled in other cohorts as well as with another cohort to correct for pathways activated by ischemia reperfusion. Using an ex-vivo cell-based assay in which human podocytes were cultured in the presence of sera from patients with recurrent and non recurrent FSGS, the molecular signature of podocytes exposed to sera from patients with REC was compared to the one established from patients with NON REC. We demonstrate that inflammatory pathways, including the TNF pathway, are primarily activated immediately after exposure to the sera of patients with primary FSGS, while phagocytotic pathways are activated when proteinuria becomes clinically evident. The TNF pathway activation by one or more circulating factors present in the sera of patients with FSGS supports prior experimental findings from our group demonstrating a causative role of local TNF in podocyte injury in FSGS. Correlation analysis with clinical and histological parameters of disease was performed and further supported a possible role for TNF pathway activation in FSGS. Additionally, we identified a unique set of genes that is specifically activated in podocytes when cultured in the presence of serum of patients with REC FSGS. This clinical translational study supports our prior experimental findings describing a potential role of the TNF pathway in the pathogenesis of FSGS. Validation of these findings in larger cohorts may lay the ground for the implementation of integrated system biology approaches to risk stratify patients affected by FSGS and to identify novel pathways relevant to podocyte injury.

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Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

Cited by 14 publications

References 38 publications

Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

Mutations in MME cause an autosomal‐recessive Charcot–Marie–Tooth disease type 2

<p>Expression Levels of miR-30c and miR-186 in Adult Patients with Membranous Glomerulonephritis and Focal Segmental Glomerulosclerosis</p>

Identification of glomerular and podocyte-specific genes and pathways activated by sera of patients with focal segmental glomerulosclerosis

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