A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease

Ronco, Pierre; Dębiec, Hanna

doi:10.1007/s00424-017-2007-x

Cited by 13 publications

(7 citation statements)

References 64 publications

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“…In MN, following autoantibody binding, several mechanisms are triggered in podocytes, like the complement signaling 54 that can lead to delocalization of nephrin with loss of the slit diaphragm structure and podocyte injury 55 . Indeed, following exposure to MN serum, we confirmed an increase in the expression of C3d protein in the three podocyte lines that, although not significant, suggests an activation of the complement pathway consistent with the in vivo cascade signaling 54,56 (Fig. 6e, f).…”

Section: Resultsmentioning

confidence: 99%

A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier

et al. 2019

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In this work we model the glomerular filtration barrier, the structure responsible for filtering the blood and preventing the loss of proteins, using human podocytes and glomerular endothelial cells seeded into microfluidic chips. In long-term cultures, cells maintain their morphology, form capillary-like structures and express slit diaphragm proteins. This system recapitulates functions and structure of the glomerulus, including permselectivity. When exposed to sera from patients with anti-podocyte autoantibodies, the chips show albuminuria proportional to patients’ proteinuria, phenomenon not observed with sera from healthy controls or individuals with primary podocyte defects. We also show its applicability for renal disease modeling and drug testing. A total of 2000 independent chips were analyzed, supporting high reproducibility and validation of the system for high-throughput screening of therapeutic compounds. The study of the patho-physiology of the glomerulus and identification of therapeutic targets are also feasible using this chip.

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Section: Resultsmentioning

confidence: 99%

A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier

et al. 2019

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“…This was observed in both the single pixel spectra and the spectra generated from an average of five pixels ( Figure S1, Supporting Information).The ability to visualize the proteins present in each of the single cell types from within the glomeruli may have direct pathological relevance to MN in particular. In this disease, for example, podocytes are the target of circulating autoantibodies, such as Phospholipase A2 receptor and Thrombospondin type 1 containing 7A domain, [24] and, while immune deposits at the mesangial cells are variable in MN, there is evidence to suggest that they may be implicated in inflammatory processes. [25] When comparing the tryptic peptide profiles of epithelial cells of the proximal and distal tubules (Figure 4), only 74.77% of the detected peaks were present in both.…”

Section: Discussionmentioning

confidence: 99%

High Spatial Resolution MALDI‐MS Imaging in the Study of Membranous Nephropathy

Smith

L’Imperio

Denti

et al. 2018

Proteomics Clinical Apps

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Purpose Matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) technology has advanced rapidly during recent years with the development of instruments equipped with low‐diameter lasers that are suitable for high spatial resolution imaging. This may provide significant advantages in certain fields of molecular pathology where more specific protein fingerprints of individual cell types are required, such as renal pathology. Experimental design Here MALDI‐MSI analysis of a cohort of membranous nephropathy (MN) patients is performed among which patients either responded favorably (R; n = 6), or unfavorably (NR; n = 4), to immunosuppressive treatment (Ponticelli Regimen), employing a 10 µm laser spot diameter. Results Specific tryptic peptide profiles of the different cellular regions within the glomerulus can be generated, similarly for the epithelial cells belonging to the proximal and distal tubules. Conversely, specific glomerular and sub‐glomerular profiles cannot be obtained while using the pixel size performed in previous studies (50 µm). Furthermore, two proteins are highlighted, sonic hedgehog and α‐smooth muscle actin, whose signal intensity and spatial localization within the sub‐glomerular and tubulointerstitial compartments differ between treatment responders and non‐responders. Conclusions and clinical relevance The present study exemplifies the advantage of using high spatial resolution MALDI‐MSI for the study of MN and highlights that such findings have the potential to provide complementary support in the routine prognostic assessment of MN patients.

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“…As a result, subepithelial deposits composed of antigen-antibody complexes are formed, along with exogenous nonpodocyte proteins, such as complement components. 5 In this process, cell-surface adhesion protein contacts can be damaged or modulated; this affects podocyte cell adhesion but also the organization of FP morphology and reduces their interdigitation-a process termed podocyte FP effacement (FPE). 6 FPE impairs the organization and integrity of the SD and, consequently, normal filtration functioning.…”

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confidence: 99%

ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage

Sachs

Wetzel

Reichelt

et al. 2021

JASN

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BackgroundPodocytes embrace the glomerular capillaries with foot processes, which are interconnected by a specialized adherens junction to ultimately form the filtration barrier. Altered adhesion and loss are common features of podocyte injury, which could be mediated by shedding of cell-adhesion molecules through the regulated activity of cell surface–expressed proteases. A Disintegrin and Metalloproteinase 10 (ADAM10) is such a protease known to mediate ectodomain shedding of adhesion molecules, among others. Here we evaluate the involvement of ADAM10 in the process of antibody-induced podocyte injury.MethodsMembrane proteomics, immunoblotting, high-resolution microscopy, and immunogold electron microscopy were used to analyze human and murine podocyte ADAM10 expression in health and kidney injury. The functionality of ADAM10 ectodomain shedding for podocyte development and injury was analyzed, in vitro and in vivo, in the anti-podocyte nephritis (APN) model in podocyte-specific, ADAM10-deficient mice.ResultsADAM10 is selectively localized at foot processes of murine podocytes and its expression is dispensable for podocyte development. Podocyte ADAM10 expression is induced in the setting of antibody-mediated injury in humans and mice. Podocyte ADAM10 deficiency attenuates the clinical course of APN and preserves the morphologic integrity of podocytes, despite subepithelial immune-deposit formation. Functionally, ADAM10-related ectodomain shedding results in cleavage of the cell-adhesion proteins N- and P-cadherin, thus decreasing their injury-related surface levels. This favors podocyte loss and the activation of downstream signaling events through the Wnt signaling pathway in an ADAM10-dependent manner.ConclusionsADAM10-mediated ectodomain shedding of injury-related cadherins drives podocyte injury.

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A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease

Cited by 13 publications

References 64 publications

A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier

A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier

High Spatial Resolution MALDI‐MS Imaging in the Study of Membranous Nephropathy

ADAM10-Mediated Ectodomain Shedding Is an Essential Driver of Podocyte Damage

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