New structural insights into podocyte biology

Grahammer, Florian

doi:10.1007/s00441-017-2590-3

Cited by 24 publications

(21 citation statements)

References 38 publications

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“…Primary membranous nephropathy (PMN) is the most common cause of nephrotic syndrome in the adult population [ 1 , 2 ] and it is one of the most common diseases affecting the glomerulus [ 2 ]. The kidney filtration barrier consists of capillary endothelial cells, glomerular basement membrane and highly specialized epithelial cell, the podocytes [ 3 , 4 ]. In patients with PMN, this filtration barrier is injured, leading to massive loss of proteins in urine (proteinuria) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

Pang

et al. 2018

Clin Proteom

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BackgroundPrimary membranous nephropathy (PMN) is an important cause of nephrotic syndrome in adults. Urine proteome may provide important clues of pathophysiological mechanisms in PMN. In the current study, we analyzed and compared the proteome of urine from patients with PMN and normal controls.MethodsWe performed two technical replicates (TMT1 and TMT2) to analyze and compare the urine proteome from patients with PMN and normal controls by tandem mass tag (TMT) technology coupled with nanoscale liquid chromatography tandem mass spectrometry analysis (LC–MS/MS). Gene ontology (GO) enrichment analysis was performed to analyse general characterization of the proteins. The proteins were also matched against the database of Kyoto Encyclopedia of Genes and Genomes (KEGG). For validation, Western blot was used to analyze the selected proteins.ResultsA total of 509 proteins and 411 proteins were identified in TMT1 and TMT2, respectively. 249 proteins were both identified in two technical replicates. GO analysis and KEGG analysis revealed immunization and coagulation were predominantly involved. Among the differential protein, the overexcretion of alpha-1-antitrypsin (A1AT) and afamin (AFM) were validated by Western blot analysis.ConclusionsOur data showed the important role of immunologic mechanism in the development of PMN, and the value of urinary A1AT and AFM in biomarker discovery of patients with PMN. The discovery of the overexcretion of A1AT and AFM in the urine can help to further elucidate pathogenetic mechanisms involved in PMN.Electronic supplementary materialThe online version of this article (10.1186/s12014-018-9183-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

Pang

et al. 2018

Clin Proteom

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“…In addition to the glomerular endothelial cells, the filtration process implies specialised cells, the podocytes that cover the capillary. The structural organisation of the podocyte that displays an interdigitating structure (foot process) assures a selective filtration of molecules depending on their size [1]. Considering that the cut-off is around 70 kDa, the finding of albumin in urine is the first symptom of glomerular filtration dysfunction that could be observed in numerous pathologies [2].…”

Section: Introductionmentioning

confidence: 99%

Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations

Delézay

Hé

Hodin

et al. 2017

Experimental Cell Research

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The kidney is an organ that plays a major role in the excretion of numerous compounds such as drugs and chemicals. However, a great number of pharmacological molecules are nephrotoxic, affecting the efficiency of the treatment and increasing morbidity or mortality. Focusing on glomerular filtration, we propose in this study a simple and reproducible in vitro human model that is able to bring to light a functional podocyte injury, correlated with morphologic/phenotypic changes after drug exposure. This model was used for the evaluation of paracellular permeability of FITC-dextran molecules as well as FITC-BSA after different treatments. Puromycin aminonucleoside and adriamycin, compounds known to induce proteinuria in vivo and that serve here as positive nephrotoxic drug controls, were able to induce an important increase in fluorescent probe passage through the cell monolayer. Different molecules were then evaluated for their potential effect on podocyte filtration. Our results demonstrated that a drug effect could be time dependent, stable or scalable and relatively specific. Immunofluorescence studies indicated that these functional perturbations were due to cytoskeletal perturbations, monolayer disassembly or could be correlated with a decrease in nephrin expression and/or ZO-1 relocation. Taken together, our results demonstrated that this in vitro human model represents an interesting tool for the screening of the renal toxicity of drugs.

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“…Among the small set of genes associated with the sequence preferred by the DDS-mutant M342R in ZF1 (Figure 6E ), MafB is in the center of a WT1-dependent transcription factor network in control of podocyte gene expression ( 45 , 68 ) [podocytes are pericytes that help to form the glomerular basement membrane in developing kidneys ( 69 )]. The Rcsd1 gene codes for a protein kinase substrate ( 70 ) and is involved in cell ability to remodel actin filament assembly and remodeling of the actin cytoskeleton, which is an important step in mitosis.…”

Section: Discussionmentioning

confidence: 99%

Role for first zinc finger of WT1 in DNA sequence specificity: Denys–Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites

Wang

Horton

Zheng³

et al. 2017

Nucleic Acids Research

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Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1–4). An alternative splicing of Wt1 can add three additional amino acids—lysine (K), threonine (T) and serine (S)—between ZF3 and ZF4. In the −KTS isoform, ZF2–4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type −KTS isoform ZF1–4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2–4, ZF1 can be positioned continuously in the DNA major groove forming a ‘near-cognate’ complex. Second, while ZF2–4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys–Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.

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New structural insights into podocyte biology

Cited by 24 publications

References 38 publications

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations

Role for first zinc finger of WT1 in DNA sequence specificity: Denys–Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites

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