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 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

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.

Giant cell formation: the way to cell death or cell survival?

2011 ◽  
Vol 6 (5) ◽  
pp. 675-684 ◽  
Author(s):  
Rostyslav Horbay ◽  
Rostyslav Stoika
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Giant Cell ◽  
Cell Formation ◽  
Giant Cells ◽  
Cancer Development ◽  
Mitotic Catastrophe ◽  
Giant Cell Formation ◽  
Cycle Disorders

AbstractThe study of giant cells in populations of different tumor cells and evaluation of their role in cancer development is an expanding field. The formation of giant cells has been shown to be followed by mitotic catastrophe, apoptosis, necrosis, and other types of cell elimination. Reports also demonstrate that giant cells can escape cell death and give rise to new cancer cells. However, it is not known if the programmed cell death is involved in this type of cell cycle disorders. Here we describe principal events that are observed during giant cell formation. We also consider the role of giant cells in cancer development, taking into account both published work and our own recent data in this field.

scholarly journals Deficiency of VCP-Interacting Membrane Selenoprotein (VIMP) Leads to G1 Cell Cycle Arrest and Cell Death in MIN6 Insulinoma Cells

2018 ◽  
Vol 51 (5) ◽  
pp. 2185-2197 ◽  
Author(s):  
Lili Men ◽  
Juan Sun ◽  
Decheng Ren
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Insulin Secretion ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Insulinoma Cells

Background/Aims: VCP-interacting membrane selenoprotein (VIMP), an ER resident selenoprotein, is highly expressed in β-cells, however, the role of VIMP in β-cells has not been characterized. In this study, we studied the relationship between VIMP deficiency and β-cell survival in MIN6 insulinoma cells. Methods: To determine the role of VIMP in β-cells, lentiviral VIMP shRNAs were used to knock down (KD) expression of VIMP in MIN6 cells. Cell death was quantified by propidium iodide (PI) staining followed by flow cytometric analyses using a FACS Caliber and FlowJo software. Cell apoptosis and proliferation were determined by TUNEL assay and Ki67 staining, respectively. Cell cycle was analyzed after PI staining. Results: The results show that 1) VIMP suppression induces β-cell apoptosis, which is associated with a decrease in Bcl-xL, and the β-cell apoptosis induced by VIMP suppression can be inhibited by overexpression of Bcl-xL; 2) VIMP knockdown (KD) decreases cell proliferation and G1 cell cycle arrest by accumulating p27 and decreasing E2F1; 3) VIMP KD suppresses unfolded protein response (UPR) activation by regulating the IRE1α and PERK pathways; 4) VIMP KD increases insulin secretion. Conclusion: These results suggest that VIMP may function as a novel regulator to modulate β-cell survival, proliferation, cell cycle, UPR and insulin secretion in MIN6 cells.

scholarly journals Assessment of TRPV4 Channel and Its Role in Colorectal Cancer Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 629-638
Author(s):  
N. N. Bahari ◽  
S. Y. N. Jamaludin ◽  
A. H. Jahidin ◽  
M. N. Zahary ◽  
A. B. Mohd Hilmi
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Colorectal Cancer ◽  
Expression Levels ◽  
Pharmacological Modulation ◽  
Colorectal Cancer Cells ◽  
Ht 29

The transient receptor potential vanilloid member 4 (TRPV4) is a non-selective calcium (Ca2+)-permeable channel which is widely expressed in different types of tissues including the lungs, liver, kidneys and salivary gland. TRPV4 has been shown to serve as a cellular sensor where it is involved in processes such as osmoregulation, cell volume regulation and thermoregulation. Emerging evidence suggests that TRPV4 also plays important roles in several aspects of cancer progression. Despite the reported roles of TRPV4 in several forms of cancers, the role of TRPV4 in human colorectal cancer remains largely unexplored. In the present study, we sought to establish the potential role of TRPV4 in colorectal cancer by assessing TRPV4 expression levels and investigating whether TRPV4 pharmacological modulation may alter cell proliferation, cell cycle and cell death in colorectal cancer cells. Quantitative real-time PCR analysis revealed that TRPV4 mRNA levels were significantly lower in HT-29 cells than normal colon CCD-18Co cells. However, TRPV4 mRNA was absent in HCT-116 cells. Pharmacological activation of TRPV4 with GSK1016790A significantly enhanced the proliferation of HT-29 cells while TRPV4 inhibition using RN 1734 decreased their proliferation. Increased proliferation in GSK1016790A-treated HT-29 cells was attenuated by co-treatment with RN 1734. Pharmacological modulation of TRPV4 had no effect on the cell cycle progression but promoted cell death in HT-29 cells. Taken together, these findings suggest differential TRPV4 expression levels in human colorectal cancer cells and that pharmacological modulation of TRPV4 produces distinct effects on the proliferation and induces cell death in HT-29 cells.

scholarly journals Role of D-GADD45 in JNK-Dependent Apoptosis and Regeneration in Drosophila

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 378 ◽  
Author(s):  
Carlos Camilleri-Robles ◽  
Florenci Serras ◽  
Montserrat Corominas
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Control ◽  
Imaginal Discs ◽  
Cellular Functions ◽  
Correct Function ◽  
Response To Stress ◽  
Wing Imaginal Discs ◽  
Harmful Effects

The GADD45 proteins are induced in response to stress and have been implicated in the regulation of several cellular functions, including DNA repair, cell cycle control, senescence, and apoptosis. In this study, we investigate the role of D-GADD45 during Drosophila development and regeneration of the wing imaginal discs. We find that higher expression of D-GADD45 results in JNK-dependent apoptosis, while its temporary expression does not have harmful effects. Moreover, D-GADD45 is required for proper regeneration of wing imaginal discs. Our findings demonstrate that a tight regulation of D-GADD45 levels is required for its correct function both, in development and during the stress response after cell death.

Protective role of low-dose TGF-β1 in early diabetic nephropathy induced by streptozotocin

2013 ◽  
Vol 17 (3) ◽  
pp. 752-758 ◽  
Author(s):  
Xiaodong Ma ◽  
Jingjing Ding ◽  
Haiyan Min ◽  
Yanting Wen ◽  
Qian Gao
Keyword(s):  
Diabetic Nephropathy ◽  
Low Dose ◽  
Protective Role ◽  
Early Diabetic Nephropathy ◽  
Tgf Β1

MicroRNA-1225-5p acts as a tumor-suppressor in laryngeal cancer via targeting CDC14B

2019 ◽  
Vol 400 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Peng Sun ◽  
Dan Zhang ◽  
Haiping Huang ◽  
Yafeng Yu ◽  
Zhendong Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Cell Division ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Normal Tissues ◽  
Cycle Arrest ◽  
Enhanced Expression ◽  
Insight Into

Abstract This study aimed to investigate the role of miRNA-1225-5p (miR-1225) in laryngeal carcinoma (LC). We found that the expression of miR-1225 was suppressed in human LC samples, while CDC14B (cell division cycle 14B) expression was reinforced in comparison with surrounding normal tissues. We also demonstrated that enhanced expression of miR-1225 impaired the proliferation and survival of LC cells, and resulted in G1/S cell cycle arrest. In contrast, reduced expression of miR-1225 promoted cell survival. Moreover, miR-1225 resulted in G1/S cell cycle arrest and enhanced cell death. Further, miR-1225 targets CDC14B 3′-UTR and recovery of CDC14B expression counteracted the suppressive influence of miR-1225 on LC cells. Thus, these findings offer insight into the biological and molecular mechanisms behind the development of LC.

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