scholarly journals Growth hormone induces mitotic catastrophe of glomerular podocytes and contributes to proteinuria

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Rajkishor Nishad ◽  
Dhanunjay Mukhi ◽  
Ashish Kumar Singh ◽  
Manga Motrapu ◽  
Kumaraswami Chintala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Hormone ◽  
Notch Signaling ◽  
Mitotic Catastrophe ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Cell Cycle Reentry ◽  
Filtration Barrier ◽  
Tgf Β1 ◽  
Notch Activation

AbstractGlomerular podocytes are integral members of the glomerular filtration barrier in the kidney and are crucial for glomerular permselectivity. These highly differentiated cells are vulnerable to an array of noxious stimuli that prevail in several glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetes. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. Previous studies have shown that podocytes express GH receptor (GHR) and induce Notch signaling when exposed to GH. In the present study, we demonstrated that GH induces TGF-β1 signaling and provokes cell cycle reentry of otherwise quiescent podocytes. Though differentiated podocytes reenter the cell cycle in response to GH and TGF-β1, they cannot accomplish cytokinesis, despite karyokinesis. Owing to this aberrant cell cycle event, GH- or TGF-β1-treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of JAK2, TGFBR1 (TGF-β receptor 1), or Notch prevented cell cycle reentry of podocytes and protected them from mitotic catastrophe associated with cell death. Inhibition of Notch activation prevents GH-dependent podocyte injury and proteinuria. Similarly, attenuation of GHR expression abated Notch activation in podocytes. Kidney biopsy sections from patients with diabetic nephropathy (DN) show activation of Notch signaling and binucleated podocytes. These data indicate that excess GH induced TGF-β1-dependent Notch1 signaling contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signaling in podocytopathy and the potential application of TGF-β1 or Notch inhibitors, as a therapeutic agent for DN.

scholarly journals Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

2019 ◽  
Author(s):  
Rajkishor Nishad ◽  
Dhanunjay Mukhi ◽  
Ashish Kumar Singh ◽  
Kumaraswami Chintala ◽  
Prasad Tammineni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Hormone ◽  
Cell Death ◽  
Diabetic Nephropathy ◽  
Notch Signaling ◽  
Mitotic Catastrophe ◽  
Podocyte Injury ◽  
Tgf Β1 ◽  
Notch Activation

AbstractPodocytes are integral members of the filtration barrier in the kidney and are crucial for glomerular permselectivity. Podocytes are highly differentiated and vulnerable to an array of noxious stimuli during various clinical conditions whereas podocyte loss plays a key role in progressive glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetics. Previous studies have shown that podocytes express GH receptors (GHR), and induce Notch signaling when exposed to GH. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. In the present study, we demonstrate that GH induces cognate TGF-β1 signaling and provokes cell cycle re-entry of otherwise quiescent podocytes. Though, differentiated podocytes re-enter the cell cycle in response to GH and TGF-β1 unable to accomplish cytokinesis, despite nuclear division. Owing to this aberrant cell-cycle events significant amount of GH or TGF-β1 treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of GHR, TGFBR1, or Notch signaling prevented cell cycle re-entry and protects podocyte from cell death. Furthermore, inhibition of Notch activation prevents GH-dependent podocyte injury and proteinuria. Kidney biopsy sections from patients with diabetic nephropathy show activation of Notch signaling and bi-nucleated podocytes. All these data confirm that excess GH induces Notch1 signaling via TGF-β1 and contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signaling in the podocytopathy and the potential application of inhibitors of TGF-β1 or Notch inhibitors as a therapeutic agent for diabetic nephropathy.Significance StatementElevated circulating levels of growth hormone (GH) associated with glomerular hypertrophy and proteinuria. Whereas decreased GH action protected against proteinuria. Podocytes are highly differentiated cells that play a vital role in glomerular filtration and curb protein loss. The direct role of GH in podocytes is the focus of our study. We found that GH induces TGF-β1 and both provoke cell cycle re-entry of podocytes in Notch1 dependent manner. Notch activation enables the podocytes to accomplish karyokinesis, but not cytokinesis owing to which podocytes remain binucleated. Binucleated podocytes that were observed during GH/TGF-β1 treatment are susceptible to cell death. Our study highlighted the fact that enforcing the differentiated podocytes to re-enter the cell cycle results in mitotic catastrophe and permanent loss.

scholarly journals Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

2021 ◽  
Author(s):  
Anil Kumar Pasupulati ◽  
Rajkishor Nishad ◽  
Dhanunjay Mukhi ◽  
Ashish Singh ◽  
Manga Motrapu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Hormone ◽  
Diabetic Nephropathy ◽  
Notch Signalling ◽  
Mitotic Catastrophe ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Differentiated Cells ◽  
Filtration Barrier ◽  
Tgf Β1

Abstract Glomerular podocytes are integral members of the glomerular filtration barrier in the kidney and are crucial for glomerular permselectivity. These highly differentiated cells are vulnerable to an array of noxious stimuli that prevail in several glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetes. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. Previous studies have shown that podocytes express GH receptor (GHR) and induce Notch signalling when exposed to GH. In the present study, we demonstrate that GH induces TGF-β1 signalling and provokes cell cycle re-entry of otherwise quiescent podocytes. Though differentiated podocytes re-enter the cell cycle in response to GH and TGF-β1, they cannot accomplish cytokinesis, despite karyokinesis. Owing to this aberrant cell-cycle event, GH or TGF-β1 treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of JAK2, TGFBR1, or Notch prevented cell cycle re-entry of podocytes and protected from mitotic catastrophe associated cell death. Inhibition of Notch ac-tivation prevents GH-dependent podocyte injury and proteinuria. Similarly, attenuation of GHR expression abated Notch activation in podocytes. Kidney biopsy sections from patients with diabetic nephropathy show activation of Notch signalling and bi-nucleated podocytes. These data indicate that excess GH induced TGF-β1 dependent Notch1 signalling contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signalling in podocytopathy and the potential application of TGF-β1 or Notch inhibitors as a therapeutic agent for diabetic nephropathy.

scholarly journals Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress

2016 ◽  
Vol 311 (6) ◽  
pp. F1308-F1317 ◽  
Author(s):  
Leopoldo Raij ◽  
Runxia Tian ◽  
Jenny S. Wong ◽  
John C. He ◽  
Kirk N. Campbell
Keyword(s):  
Oxidative Stress ◽  
Glomerular Filtration ◽  
Biologically Active ◽  
Current Evidence ◽  
Glomerular Sclerosis ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Focal Segmental Glomerular Sclerosis

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap −/− model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2−) that promotes endothelin-1 synthesis. Plg via O2− also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a “second hit” in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.

scholarly journals Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

2015 ◽  
Vol 22 (11) ◽  
pp. 1775-1784 ◽  
Author(s):  
S Marathe ◽  
S Liu ◽  
E Brai ◽  
M Kaczarowski ◽  
L Alberi
Keyword(s):  
Cell Cycle ◽  
Notch Signaling ◽  
Cell Cycle Reentry

WT1-interacting protein and ZO-1 translocate into podocyte nuclei after puromycin aminonucleoside treatment

2005 ◽  
Vol 289 (2) ◽  
pp. F431-F441 ◽  
Author(s):  
Maribel Rico ◽  
Amitava Mukherjee ◽  
Martha Konieczkowski ◽  
Leslie A. Bruggeman ◽  
R. Tyler Miller ◽  
...  
Keyword(s):  
Adherens Junctions ◽  
Slit Diaphragm ◽  
Cell Junctions ◽  
Puromycin Aminonucleoside ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Interacting Protein ◽  
Filtration Barrier ◽  
Cell Cell

Podocyte differentiation is required for normal glomerular filtration barrier function and is regulated by the transcription factor WT1. We identified WT1-interacting protein (WTIP) and hypothesized that it functions as both a scaffold for slit diaphragm proteins and a corepressor of WT1 transcriptional activity by shuttling from cell-cell junctions to the nucleus after injury. Endogenous WTIP colocalizes with zonula occludens-1 (ZO-1) in cultured mouse podocyte adherens junctions. To model podocyte injury in vitro, we incubated differentiated podocytes with puromycin aminonucleoside (PAN; 100 μg/ml) for 24 h, which disassembled cell-cell contacts, rearranged actin cytoskeleton, and caused process retraction. Podocyte synaptopodin expression diminished after PAN treatment, consistent with podocyte dedifferentiation in some human glomerular diseases. To assess podocyte function, we measured albumin flux across differentiated podocytes cultured on collagen-coated Transwell filters. Albumin transit across PAN-treated cells increased to levels observed with undifferentiated podocytes. Consistent with our hypothesis, WTIP, as well as ZO-1, translocated from podocyte adherens junctions to nuclei in PAN-treated cells. Because WTIP is a transcriptional corepressor for WT1, we examined the effect of PAN on expression of retinoblastoma binding protein Rbbp7 (also known as RbAp46), a WT1 target gene expressed in S-shaped bodies during nephrogenesis. Rbbp7 expression in PAN-treated podocytes was reduced compared with untreated cells. In conclusion, WTIP translocates from cell-cell junctions to the nucleus in PAN-treated podocytes. We suggest that WTIP monitors slit diaphragm protein assembly and shuttles into the nucleus after podocyte injury, translating changes in slit diaphragm structure into altered gene expression and a less differentiated phenotype.

Notch/HES1 Signaling Stabilizes p53 Expression Via a Novel PARP1-Chfr-PLK1-Mediated Mechanism in B-ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1292-1292
Author(s):  
Sankaranarayanan Kannan ◽  
Patrick A Zweidler-McKay
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Critical Role ◽  
Growth Arrest ◽  
Cyclin B ◽  
Cell Type ◽  
Cell Type Specific ◽  
Notch Activation

Abstract Abstract 1292 Background: Notch signaling contributes to T cell leukemogenesis. However, we have found that activation of Notch signaling in human B-ALL promotes growth arrest and apoptosis. These contrasting effects of Notch in B versus T cell ALL, mirror effects seen in early lymphocyte development. As the Notch receptors are common between T and B cells, we hypothesized that these differences rely on the cell-type specific downstream mechanisms. We previously reported a critical role for Notch/HES1-mediated activation of Poly ADP-Ribose Polymerase 1 (PARP1) function in this B cell specific mechanism. Approach: To explore the cell-type specific downstream mechanisms of Notch activation in B-ALL, we used cell fractionation, westerns and immunoprecipitation to identify cell cycle regulators which were altered by Notch activation via HES1 expression in human B-ALL lines. Results: Notch activation in a panel of human B-ALL lines led to consistent growth arrest and apoptosis. Indeed, ligands, activated receptors and the Notch target gene HES1 all induced these leukemia lihibiting effects in B-ALL but not T-ALL lines. In this study we report a mechanism whereby HES1-mediated activation of PARP1 leads to PARylation of the E3 ligase Checkpoint with FHA and RING finger (CHFR) (Panel A) which results in targeting and ubiquitination of the cell cycle regulator Polo-Like Kinase 1 (PLK1) (Panel B). PLK1 is highly expressed in B vs. T-ALL and plays a critical role in B cell growth and survival. Following Notch activation, loss of ubiquitionated PLK1 through proteosomal degradation leads to cell cycle arrest through two mechanisms, namely cytoplasmic relocalization of cyclin B, disrupting the CDC2-cyclinB complex, as well as phosphorylation of p53 at S20, which leads to decreased weakened p53-MDM2 interaction and accumulation of p53 (Panel C). siRNA to CHFR reveal that this mechanism is dependent on CHFR (Panel C). Importantly this mechanism is not seen in T-ALL cells as the activation of PARP1 by HES1 does not occur in T-ALL cells. Conclusions: Our findings reveal a novel molecular mechanism whereby Notch signaling induces disruption of the cell cycle in a cell type specific manner in B-ALL. Activation of PARP1, PARylation of CHFR, ubiquitination of PLK1 resulting in loss of nuclear cyclin B and accumulation of p53 demonstrates a series of events which can be initiated through activation of Notch in B-ALL. This mechanism reveals a potentially targetable approach to B-ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury

2015 ◽  
Vol 36 (4) ◽  
pp. 596-614 ◽  
Author(s):  
Rakesh Verma ◽  
Madhusudan Venkatareddy ◽  
Anne Kalinowski ◽  
Sanjeevkumar R. Patel ◽  
David J. Salant ◽  
...  
Keyword(s):  
Cell Culture ◽  
Tyrosine Phosphorylation ◽  
Sh2 Domain ◽  
Slit Diaphragm ◽  
Dependent Manner ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Signaling Events ◽  
Foot Process

In most forms of glomerular diseases, loss of size selectivity by the kidney filtration barrier is associated with changes in the morphology of podocytes. The kidney filtration barrier is comprised of the endothelial lining, the glomerular basement membrane, and the podocyte intercellular junction, or slit diaphragm. The cell adhesion proteins nephrin and neph1 localize to the slit diaphragm and transduce signals in a Src family kinase Fyn-mediated tyrosine phosphorylation-dependent manner. Studies in cell culture suggest nephrin phosphorylation-dependent signaling events are primarily involved in regulation of actin dynamics and lamellipodium formation. Nephrin phosphorylation is a proximal event that occurs both during development and following podocyte injury. We hypothesized that abrogation of nephrin phosphorylation following injury would prevent nephrin-dependent actin remodeling and foot process morphological changes. Utilizing a biased screening approach, we found nonreceptor Src homology 2 (sh2) domain-containing phosphatase Shp2 to be associated with phosphorylated nephrin. We observed an increase in nephrin tyrosine phosphorylation in the presence of Shp2 in cell culture studies. In the human glomerulopathies minimal-change nephrosis and membranous nephropathy, there is an increase in Shp2 phosphorylation, a marker of increased Shp2 activity. Mouse podocytes lacking Shp2 do not develop foot process spreading when subjected to podocyte injuryin vivousing protamine sulfate or nephrotoxic serum (NTS). In the NTS model, we observed a lack of foot process spreading in mouse podocytes with Shp2 deleted and smaller amounts of proteinuria. Taken together, these results suggest that Shp2-dependent signaling events are necessary for changes in foot process structure and function following injury.

scholarly journals Podocyte Autophagy in Homeostasis and Disease

2021 ◽  
Vol 10 (6) ◽  
pp. 1184
Author(s):  
Qisheng Lin ◽  
Khadija Banu ◽  
Zhaohui Ni ◽  
Jeremy S. Leventhal ◽  
Madhav C. Menon
Keyword(s):  
Glomerular Filtration ◽  
Functional Role ◽  
Specific Reference ◽  
Protective Mechanism ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Cellular Autophagy ◽  
Survival Mechanisms

Autophagy is a protective mechanism that removes dysfunctional components and provides nutrition for cells. Podocytes are terminally differentiated specialized epithelial cells that wrap around the capillaries of the glomerular filtration barrier and show high autophagy level at the baseline. Here, we provide an overview of cellular autophagy and its regulation in homeostasis with specific reference to podocytes. We discuss recent data that have focused on the functional role and regulation of autophagy during podocyte injury in experimental and clinical glomerular diseases. A thorough understanding of podocyte autophagy could shed novel insights into podocyte survival mechanisms with injury and offer potential targets for novel therapeutics for glomerular disease.

scholarly journals The podocyte as a direct target for treatment of glomerular disease?

2016 ◽  
Vol 311 (1) ◽  
pp. F46-F51 ◽  
Author(s):  
Sandeep K. Mallipattu ◽  
John C. He
Keyword(s):  
The United States ◽  
Glomerular Disease ◽  
Glomerular Sclerosis ◽  
Systemic Effects ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Filtration Barrier ◽  
Focal Segmental Glomerular Sclerosis ◽  
Control And Prevention ◽  
Segmental Glomerular Sclerosis

The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans, have chronic kidney disease (CKD). A failure to maintain the glomerular filtration barrier directly contributes to the onset of CKD. The visceral epithelial cells, podocytes, are integral to the maintenance of this renal filtration barrier. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, and HIV-associated nephropathy (HIVAN). Since podocytes are terminally differentiated with minimal capacity to self-replicate, they are extremely sensitive to cellular injury. In the past two decades, our understanding of the mechanism(s) by which podocyte injury occurs has greatly expanded. With this newfound knowledge, therapeutic strategies have shifted to identifying targets directed specifically at the podocyte. Although the systemic effects of these agents are important, their direct effect on the podocyte proves to be essential in ameliorating glomerular disease. In this review, we highlight the mechanisms by which these agents directly target the podocyte independent of its systemic effects.

Sign in / Sign up

Export Citation Format

Share Document