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New Aspects for Understanding Podocytopathies II
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New Aspects for Understanding Podocytopathies II

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 August 2023) | Viewed by 6536

Special Issue Editor

Prof. Dr. Nicole Endlich

E-Mail Website
Guest Editor
Institute for Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
Interests: podocytes; kidney diseases; zebrafish model; glomerulus; microscopy; miRNA; actin cytoskeleton; mechanical stretch
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The success of the first edition of this Special Issue encouraged us to launch a second edition.

More than 10% of the world’s population suffers from kidney disease, and the trend is increasing. In many cases, a particular cell type in the kidney (i.e., the podocytes) is responsible for the development of both acute and chronic kidney disease. This post-mitotic cell type covers the outer aspect of the capillaries in the filtration units of the kidney, that is, the glomeruli. The loss or damage of podocytes often leads to chronic kidney disease, which results in complete organ failure. Since there are currently few treatment options for patients suffering from podocyte-associated disease and there are currently no curative drugs available, transplantation and dialysis, which are associated with a high mortality rate, are necessary for survival.

In this Special Issue, new and groundbreaking studies will be published in order to provide a perspective for future treatment of this disease. 

Prof. Dr. Nicole Endlich
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • podocytes
  • kidney diseases
  • zebrafish model
  • glomerulus
  • microscopy
  • miRNA
  • actin cytoskeleton
  • mechanical stretch

Published Papers (4 papers)

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Research

18 pages, 3400 KiB  
Article
Transcription Factor NFE2L1 Decreases in Glomerulonephropathies after Podocyte Damage
by Mustafa Elshani, In Hwa Um, Steve Leung, Paul A. Reynolds, Alex Chapman, Mary Kudsy and David J. Harrison
Cells 2023, 12(17), 2165; https://doi.org/10.3390/cells12172165 - 29 Aug 2023
Cited by 1 | Viewed by 1036
Abstract
Podocyte cellular injury and detachment from glomerular capillaries constitute a critical factor contributing to kidney disease. Notably, transcription factors are instrumental in maintaining podocyte differentiation and homeostasis. This study explores the hitherto uninvestigated expression of Nuclear Factor Erythroid 2-related Factor 1 (NFE2L1) in [...] Read more.
Podocyte cellular injury and detachment from glomerular capillaries constitute a critical factor contributing to kidney disease. Notably, transcription factors are instrumental in maintaining podocyte differentiation and homeostasis. This study explores the hitherto uninvestigated expression of Nuclear Factor Erythroid 2-related Factor 1 (NFE2L1) in podocytes. We evaluated the podocyte expression of NFE2L1, Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2), and NAD(P)H:quinone Oxidoreductase (NQO1) in 127 human glomerular disease biopsies using multiplexed immunofluorescence and image analysis. We found that both NFE2L1 and NQO1 expressions were significantly diminished across all observed renal diseases. Furthermore, we exposed human immortalized podocytes and ex vivo kidney slices to Puromycin Aminonucleoside (PAN) and characterized the NFE2L1 protein isoform expression. PAN treatment led to a reduction in the nuclear expression of NFE2L1 in ex vivo kidney slices and podocytes. Full article
(This article belongs to the Special Issue New Aspects for Understanding Podocytopathies II)
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12 pages, 1466 KiB  
Article
Ratio of Urinary Proteins to Albumin Excretion Shifts Substantially during Progression of the Podocytopathy Alport Syndrome, and Spot Urine Is a Reliable Method to Detect These Pathologic Changes
by Jan Boeckhaus, Lea Mohr, Hassan Dihazi, Burkhard Tönshoff, Lutz T. Weber, Lars Pape, Kay Latta, Henry Fehrenbach, Baerbel Lange-Sperandio, Matthias Kettwig, Hagen Staude, Sabine König, Ulrike John-Kroegel, Jutta Gellermann, Bernd Hoppe, Matthias Galiano, Dieter Haffner, Heidrun Rhode and Oliver Gross
Cells 2023, 12(9), 1333; https://doi.org/10.3390/cells12091333 - 07 May 2023
Cited by 1 | Viewed by 1591
Abstract
The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages [...] Read more.
The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30–300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75–187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was “only” about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104). Full article
(This article belongs to the Special Issue New Aspects for Understanding Podocytopathies II)
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17 pages, 3913 KiB  
Article
Capsazepine (CPZ) Inhibits TRPC6 Conductance and Is Protective in Adriamycin-Induced Nephropathy and Diabetic Glomerulopathy
by Henning Hagmann, Naghmeh Hassanzadeh Khayyat, Mahsa Matin, Cem Oezel, He Chen, Astrid Schauss, Christoph Schell, Thomas Benzing, Stuart Dryer and Paul T. Brinkkoetter
Cells 2023, 12(2), 271; https://doi.org/10.3390/cells12020271 - 10 Jan 2023
Cited by 1 | Viewed by 1642
Abstract
Reactive oxygen species (ROS), which excessively arise in diabetes and systemic inflammatory diseases, modify cellular lipids and cellular lipid composition leading to altered biophysical properties of cellular membranes. The impact of lipid peroxidation on transmembrane signaling routes is not yet well studied. The [...] Read more.
Reactive oxygen species (ROS), which excessively arise in diabetes and systemic inflammatory diseases, modify cellular lipids and cellular lipid composition leading to altered biophysical properties of cellular membranes. The impact of lipid peroxidation on transmembrane signaling routes is not yet well studied. The canonical transient receptor potential channel 6 (TRPC6) is implicated in the pathogenesis of several forms of glomerular diseases. TRPC6 is sensitive to membrane stretch and relies on a distinct lipid environment. This study investigates the effect of oxidative alterations to plasma membrane lipids on TRPC6 activity and the function of the glomerular filter. Knockout of the anti-oxidative, lipid modifying enzyme paraoxonase 2 (PON2) leads to altered biophysical properties of glomerular epithelial cells, which are called podocytes. Cortical stiffness, quantified by atomic force microscopy, was largely increased in PON2-deficient cultured podocytes. PON2 deficiency markedly enhanced TRPC6 channel currents and channel recovery. Treatment with the amphiphilic substance capsazepine in micromolar doses reduced cortical stiffness and abrogated TRPC6 conductance. In in vivo studies, capsazepine reduced the glomerular phenotype in the model of adriamycin-induced nephropathy in PON2 knockout mice and wildtype littermates. In diabetic AKITA mice, the progression of albuminuria and diabetic kidney disease was delayed. In summary, we provide evidence that the modification of membrane characteristics affects TRPC6 signaling. These results could spur future research to investigate modification of the direct lipid environment of TRPC6 as a future therapeutic strategy in glomerular disease. Full article
(This article belongs to the Special Issue New Aspects for Understanding Podocytopathies II)
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18 pages, 2836 KiB  
Article
Paraoxonase 2 (PON2) Deficiency Reproduces Lipid Alterations of Diabetic and Inflammatory Glomerular Disease and Affects TRPC6 Signaling
by Henning Hagmann, Naghmeh Hassanzadeh Khayyat, Cem Oezel, Antonios Papadakis, Alexander Kuczkowski, Thomas Benzing, Erich Gulbins, Stuart Dryer and Paul T. Brinkkoetter
Cells 2022, 11(22), 3625; https://doi.org/10.3390/cells11223625 - 16 Nov 2022
Cited by 4 | Viewed by 1594
Abstract
Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a [...] Read more.
Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a loss of terminally differentiated glomerular epithelial cells called podocytes refers to irreversible damage. Podocytes are characterized by a complex ramified cellular architecture and highly active transmembrane signaling. Alterations in lipid composition in states of disease have been described in podocytes but the pathophysiologic mechanisms mediating podocyte damage are unclear. In this study, we employ a genetic deletion of the anti-oxidative, lipid-modifying paraoxonase 2 enzyme (PON2) as a model to study altered cellular lipid composition and its effects on cellular signaling in glomerular disease. PON2 deficiency reproduces features of an altered lipid composition of glomerular disease, characterized by an increase in ceramides and cholesterol. PON2 knockout mice are more susceptible to glomerular damage in models of aggravated oxidative stress such as adriamycin-induced nephropathy. Voltage clamp experiments in cultured podocytes reveal a largely increased TRPC6 conductance after a membrane stretch in PON2 deficiency. Correspondingly, a concomitant knockout of TRPC6 and PON2 partially rescues the aggravated glomerular phenotype of a PON2 knockout in the adriamycin model. This study establishes PON2 deficiency as a model to investigate the pathophysiologic mechanisms of podocyte dysfunction related to alterations in the lipid composition, as seen in diabetic and inflammatory glomerular disease. Expanding the knowledge on these routes and options of intervention could lead to novel treatment strategies for glomerular disease. Full article
(This article belongs to the Special Issue New Aspects for Understanding Podocytopathies II)
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