Glomerular tissue extra-cellular proteome in focal segemental glomerular sclerosis
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Elite
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Michael L. Merchant, PhD
PROVIDER: MSV000084083 | MassIVE | Fri Jul 12 11:55:00 BST 2019
SECONDARY ACCESSION(S): PXD014594
REPOSITORIES: MassIVE
Similar Datasets
Project description:Obesity can initiate and accelerate the progression of kidney diseases. However, it remains unclear how obesity affects renal dysfunction. Here, we show that a newly generated podocyte-specific tubular sclerosis complex 2 (Tsc2) knockout mouse model (Tsc2∆podocyte) develops proteinuria and dies due to end-stage renal dysfunction by 10 weeks of age. Tsc2∆podocyte mice exhibit an increased glomerular size and focal segmental glomerulosclerosis, including podocyte foot process effacement, mesangial sclerosis and proteinaceous casts. Podocytes isolated from Tsc2∆podocyte mice show nuclear factor, erythroid derived 2, like 2-mediated increased oxidative stress response on microarray analysis and their autophagic activity is lowered through the mammalian target of rapamycin (mTOR)—unc-51-like kinase 1 pathway. Rapamycin attenuated podocyte dysfunction and extends survival in Tsc2∆podocyte mice. Additionally, mTOR complex 1 (mTORC1) activity is increased in podocytes of renal biopsy specimens obtained from obese patients with chronic kidney disease. Our work shows that mTORC1 hyperactivation in podocytes leads to severe renal dysfunction and that inhibition of mTORC1 activity in podocytes could be a key therapeutic target for obesity-related kidney diseases.
2020-03-21 | GSE106828 | GEO
Project description:Pilot urine peptidome study to evaluate Proteasix tool to predict proteolytic activity associated with nephrotic syndrome disease.
2019-07-12 | MSV000084084 | MassIVE
Project description: Not available
| S-EPMC8720665 | biostudies-literature
Project description:BackgroundThe Oxford classification of IgA nephropathy (IgAN) was revised in 2016 which lacked sufficient evidence for prognostic value of subclassification of focal segmental glomerular sclerosis (S lesion), and the proper proportion of S lesion for subclassification remains undetermined.AimThis study aimed to explore the predictive value of the new subclassification of S score on renal outcomes of IgAN patients.Methods348 patients with IgAN-associated S lesion were enrolled. According to the optimal cut-off of 25% established by receiver operating characteristic (ROC) curves, we divided S1 patients into two groups: S1a group (S lesion < 25%) and S1b group (S lesion ≥ 25%). IgAN patients with mild lesion (M0E0S0T0C0) were set as the control group. The clinical features at renal biopsy, pathological findings, and follow-up parameters (follow-up time ranged from 1 to 5 years) were collected. We used univariate and multivariate analyses to assess whether the subclassification of S score could refine risk prediction and clinical utility.ResultsWe demonstrated that S lesion ≥ 25% was associated with a more rapid GFR loss and a lower rate of complete remission of proteinuria even adjusted for multiple clinic pathological variables, compared to S1a group (All p values <.05). And the ratio of glomeruli with T lesion and crescents were higher in patients with S lesion ≥ 25%. Data showed that IgAN patients with S lesion ≥ 25% were at an increased risk of poor renal outcomes even with immunosuppression.ConclusionThis study might recommend new subclassification of S scores (S0 (no S lesion), S1 (S lesion <25% of glomeruli), and S2 (S lesion ≥ 25% of glomeruli)) for the Oxford classification. This model may also help to evaluate pros and cons of immunosuppressive therapy in IgAN patients with different level of S lesion.KEY MESSAGESS lesion ≥ 25% is an independent risk factor for poor renal outcome in IgAN patients.This new subclassification of S scores may help to evaluate pros and cons of immunotherapy in IgAN patients with different level of S lesion.
| S-EPMC8032344 | biostudies-literature
Project description:IntroductionGuidelines advise initial therapy with corticosteroids (CSs) in patients with presumed primary focal segmental glomerular sclerosis (pFSGS). Many patients do not achieve complete remission (CR) after 8 or 16 weeks. Although these patients are considered steroid resistant, clinical outcomes are ill defined.MethodsA retrospective cohort study of patients with pFSGS who were referred between January 1995 and December 2014. Data of clinical presentation until last follow-up were collected from patient records.ResultsA total of 51 patients (median age 47 years, 20 female/31 male) were included (median follow-up 7.1 years). There were 10 patients who achieved partial response (PR) at 8 weeks. High-dose CS monotherapy was continued for a median of 17 weeks (interquartile range [IQR] 11-21 weeks) (total duration 56 weeks [IQR 28-83 weeks]). With CSs, the cumulative incidence of CR + PR was 18% and 35%, respectively. Of 24 patients with persistent nephrotic-range proteinuria, 22 received additional immunosuppressive (IS) therapy, resulting in CR in 3 (14%) and PR in 11 patients (50%). A decrease of >20% of proteinuria at 8 weeks predicted response. In addition, 8 patients (36%) were considered primary nonresponders. A genetic cause was found in 2 patients. Proteinuria at end of follow-up was 1.2 g (IQR 0.4-3.0 g/24 hours or g/10 mmol creatinine). Renal survival at 3, 5, and 10 years was 92%, 87%, and 64%, respectively.ConclusionPatients with presumed pFSGS often respond late to IS therapy. A decrease in proteinuria of >20% after 8 weeks of therapy is a predictor of responsiveness. Regardless of CR in some patients, improved biomarkers are needed to predict response/outcomes in patients with pFSGS.
| S-EPMC8720814 | biostudies-literature
Project description:Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies.We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-?3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer.All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, ?3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-?3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar(®) Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79?mg/dL with <1?g of proteinuria.ACTH therapy was associated with improvement in renal function within 4?weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.
| S-EPMC4367432 | biostudies-other
Project description:Focal segmental glomerulosclerosis (FSGS) involves considerable histological heterogeneity in terms of location and quality of the glomerular segmental lesions. The present study investigated the heterogeneity of segmental lesions in each variant of FSGS, determined by the Columbia classification, and its clinical relevance. All glomerular segmental lesions of 80 cases of primary FSGS were evaluated histologically based on location [tip (TIP), perihilar (PH), or not otherwise specified (NOS)], and quality (cellular or fibrous). Among the 1,299 glomeruli of the 80 biopsy specimens, 210 glomeruli (16.2%) had segmental lesions, comprising 57 (27%) cellular TIP, 4 (2%) fibrous TIP, 42 (20%) cellular NOS, 86 (41%) fibrous NOS, and 21 (10%) fibrous PH lesions. Each case was also classified into one of the five histological variants of the Columbia classification: collapsing (COL), TIP, cellular (CEL), PH, or NOS. Overlap of segmental lesions in different location categories was seen in the COL, TIP, and PH variants, and heterogeneity of quality was apparent in the COL and CEL variants. Histological findings of the CEL variant (endocapillary hypercellularity) were observed in nine of the 13 COL variants. Both location and quality correlated with disease duration, degree of proteinuria, and histological severity of global glomerular sclerosis and tubulo-interstitial lesions. These results demonstrated the histological heterogeneity of glomerular segmental lesions in all variants of the Columbia classification, except NOS. However, the fidelity of location and dominance of histological features were generally conserved in the TIP and PH variants. The COL and CEL variants warrant further investigation because of their overlapping histological findings and apparent histological heterogeneity in the glomerular segmental lesions.
| S-EPMC3253997 | biostudies-literature
Project description:Podocyte-specific deletion of tubular sclerosis complex 2 causes focal segmental glomerular sclerosis and progressive renal failure
| PRJNA418148 | ENA
Project description:It has been known for some time that laminins containing ?1 and ?2 chains, which are normally restricted to the mesangial matrix, accumulate in the glomerular basement membranes (GBM) of Alport mice, dogs, and humans. We show that laminins containing the ?2 chain, but not those containing the ?1 chain activates focal adhesion kinase (FAK) on glomerular podocytes in vitro and in vivo. CD151-null mice, which have weakened podocyte adhesion to the GBM rendering these mice more susceptible to biomechanical strain in the glomerulus, also show progressive accumulation of ?2 laminins in the GBM, and podocyte FAK activation. Analysis of glomerular mRNA from both models demonstrates significant induction of MMP-9, MMP-10, MMP-12, MMPs linked to GBM destruction in Alport disease models, as well as the pro-inflammatory cytokine IL-6. SiRNA knockdown of FAK in cultured podocytes significantly reduced expression of MMP-9, MMP-10 and IL-6, but not MMP-12. Treatment of Alport mice with TAE226, a small molecule inhibitor of FAK activation, ameliorated fibrosis and glomerulosclerosis, significantly reduced proteinuria and blood urea nitrogen levels, and partially restored GBM ultrastructure. Glomerular expression of MMP-9, MMP-10 and MMP-12 mRNAs was significantly reduced in TAE226 treated animals. Collectively, this work identifies laminin ?2-mediated FAK activation in podocytes as an important early event in Alport glomerular pathogenesis and suggests that FAK inhibitors, if safe formulations can be developed, might be employed as a novel therapeutic approach for treating Alport renal disease in its early stages.
| S-EPMC4051676 | biostudies-literature
Project description:Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
2024-02-20 | GSE255958 | GEO