Abstract:Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF’s active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on p… Show more
“…Although these data originate from cells of the whole glomeruli, but are very likely influenced by podocytes, as they heavily rely on an intact Ca 2+ -actin cytoskeleton axis 14 . It is also in line with our previous in vitro experiments 11 , which we performed to exclude the impact of immune cells and study MPA’s direct effect on podocytes. Doing so, our RNA sequencing of an MPA treated podocyte cell line revealed an accumulation of terms including “calcium channel activity”, “calcium ion transport” “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction ”.…”
Section: Discussionsupporting
confidence: 85%
“…Doing so, our RNA sequencing of an MPA treated podocyte cell line revealed an accumulation of terms including “calcium channel activity”, “calcium ion transport” “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction ”. This leads potentially to normalization of [Ca 2+ ] i in podocytes and to amelioration of the disorganized actin cytoskeleton demonstrated also by immunofluorescence staining 11 . Figure 7 Molecular changes in podocytes after MMF treatment in nephrotoxic serum nephritis.…”
Section: Discussionmentioning
confidence: 87%
“…In line with that our previous in vitro experiments performing RNA sequencing of a MPA treated podocyte cell line revealed an accumulation of the terms “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction” . Additionally, also the terms “calcium channel activity” and “calcium ion transport” were enriched 11 . The rise in intracellular calcium concentration ([Ca 2+ ] i ) in podocytes 12 can lead to acute reorganization of the actin cytoskeleton or even cytoskeletal collapse and proteinuria 13 – 16 .…”
Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.
“…Although these data originate from cells of the whole glomeruli, but are very likely influenced by podocytes, as they heavily rely on an intact Ca 2+ -actin cytoskeleton axis 14 . It is also in line with our previous in vitro experiments 11 , which we performed to exclude the impact of immune cells and study MPA’s direct effect on podocytes. Doing so, our RNA sequencing of an MPA treated podocyte cell line revealed an accumulation of terms including “calcium channel activity”, “calcium ion transport” “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction ”.…”
Section: Discussionsupporting
confidence: 85%
“…Doing so, our RNA sequencing of an MPA treated podocyte cell line revealed an accumulation of terms including “calcium channel activity”, “calcium ion transport” “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction ”. This leads potentially to normalization of [Ca 2+ ] i in podocytes and to amelioration of the disorganized actin cytoskeleton demonstrated also by immunofluorescence staining 11 . Figure 7 Molecular changes in podocytes after MMF treatment in nephrotoxic serum nephritis.…”
Section: Discussionmentioning
confidence: 87%
“…In line with that our previous in vitro experiments performing RNA sequencing of a MPA treated podocyte cell line revealed an accumulation of the terms “actin cytoskeleton” and “regulation of small GTPase mediated signal transduction” . Additionally, also the terms “calcium channel activity” and “calcium ion transport” were enriched 11 . The rise in intracellular calcium concentration ([Ca 2+ ] i ) in podocytes 12 can lead to acute reorganization of the actin cytoskeleton or even cytoskeletal collapse and proteinuria 13 – 16 .…”
Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.
“…Nevertheless, several lines of research provide intriguing insights into potential modes of action. It has been suggested that one facet of MMF’s protective effect against podocyte injury could be attributed to its role in restoring the integrity of the cytoskeletal axis of actin filaments ( 169 , 170 ). Furthermore, experiments utilizing diabetic mouse models treated with MMF showed a notable reduction in the number of infiltrated CD4 and CD8 T cells within the kidneys.…”
Section: Therapeutic Strategies Targeting Immunity In Podocyte Injurymentioning
The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.
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