scholarly journals Parathyroid Hormone-Related Protein Is a Mitogenic and a Survival Factor of Mesangial Cells from Male Mice: Role of Intracrine and Paracrine Pathways

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 853-864 ◽  
Author(s):  
Mazène Hochane ◽  
Denis Raison ◽  
Catherine Coquard ◽  
Olivier Imhoff ◽  
Thierry Massfelder ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Nuclear Localization ◽  
Signal Peptide ◽  
Mesangial Cells ◽  
Nuclear Localization Sequence ◽  
Related Protein ◽  
Wild Type ◽  
Parathyroid Hormone Related Protein ◽  
Proliferation And Apoptosis ◽  
Localization Sequence

Glomerulonephritis is characterized by the proliferation and apoptosis of mesangial cells (MC). The parathyroid-hormone related protein (PTHrP) is a locally active cytokine that affects these phenomena in many cell types, through either paracrine or intracrine pathways. The aim of this study was to evaluate the effect of both PTHrP pathways on MC proliferation and apoptosis. In vitro studies were based on MC from male transgenic mice allowing PTHrP-gene excision by a CreLoxP system. MC were also transfected with different PTHrP constructs: wild type PTHrP, PTHrP devoid of its signal peptide, or of its nuclear localization sequence. The results showed that PTHrP deletion in MC reduced their proliferation even in the presence of serum and increased their apoptosis when serum-deprived. PTH1R activation by PTHrP(1–36) or PTH(1–34) had no effect on proliferation but improved MC survival. Transfection of MC with PTHrP devoid of its signal peptide significantly increased their proliferation and minimally reduced their apoptosis. Overexpression of PTHrP devoid of its nuclear localization sequence protected cells from apoptosis without changing their proliferation. Wild type PTHrP transfection conferred both mitogenic and survival effects, which seem independent of midregion and C-terminal PTHrP fragments. PTHrP-induced MC proliferation was associated with p27Kip1 down-regulation and c-Myc/E2F1 up-regulation. PTHrP increased MC survival through the activation of cAMP/protein kinase A and PI3-K/Akt pathways. These results reveal that PTHrP is a cytokine of multiple roles in MC, acting as a mitogenic factor only through an intracrine pathway, and reducing apoptosis mainly through the paracrine pathway. Thus, PTHrP appears as a probable actor in MC injuries.

scholarly journals Parathyroid hormone-related protein induces fibronectin up-regulation in rat mesangial cells through reactive oxygen species/Src/EGFR signaling

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Hong-Min Chen ◽  
Jia-Jia Dai ◽  
Rui Zhu ◽  
Fang-Fang Peng ◽  
Su-Zhen Wu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Parathyroid Hormone ◽  
Mesangial Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Related Protein ◽  
Egfr Signaling ◽  
Mesenchymal Transition ◽  
Parathyroid Hormone Related Protein ◽  
Tgf Β1

Abstract Parathyroid hormone-related protein (PTHrP) is known to be up-regulated in both glomeruli and tubules in patients with diabetic kidney disease (DKD), but its role remains unclear. Previous studies show that PTHrP-induced hypertrophic response in mesangial cells (MCs) and epithelial-mesenchymal transition (EMT) in tubuloepithelial cells can be mediated by TGF-β1. In the present study, although long-term PHTrP (1–34) treatment increased the mRNA and protein level of TGF-β1 in primary rat MCs, fibronectin up-regulation occurred earlier, suggesting that fibronectin induction is independent of TGF-β1/Smad signaling. We thus evaluated the involvement of epidermal growth factor receptor (EGFR) signaling and found that nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species mediates PTHrP (1–34)-induced Src kinase activation. Src phosphorylates EGFR at tyrosine 845 and then transactive EGFR. Subsequent PI3K activation mediates Akt and ERK1/2 activation. Akt and ERK1/2 discretely lead to excessive protein synthesis of fibronectin. Our study thus demonstrates the new role of PTHrP in fibronectin up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for glomerular sclerosis.

Placental adaptive up-regulation of calcium transport in wild-type mice is not driven by parathyroid hormone-related protein (PTHrP)

Placenta ◽  
2016 ◽  
Vol 45 ◽  
pp. 128
Author(s):  
Christina Hayward ◽  
Kirsty McIntyre ◽  
Colin Sibley ◽  
Susan Greenwood ◽  
Mark Dilworth
Keyword(s):  
Parathyroid Hormone ◽  
Calcium Transport ◽  
Related Protein ◽  
Wild Type ◽  
Parathyroid Hormone Related Protein

scholarly journals PTHrP Nuclear Localization and Carboxyl Terminus Sequences Modulate Dental and Mandibular Development in Part via the Action of p27

Endocrinology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 72-84 ◽  
Author(s):  
Wen Sun ◽  
Jun Wu ◽  
Linying Huang ◽  
Hong Liu ◽  
Rong Wang ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Alveolar Bone ◽  
Bone Volume ◽  
Carboxyl Terminus ◽  
Nuclear Localization Sequence ◽  
Wild Type ◽  
Mineral Density ◽  
C Terminus ◽  
Localization Sequence ◽  
Dentin Sialoprotein

Abstract To determine whether the action of the PTHrP nuclear localization sequence and C terminus is mediated through p27 in modulating dental and mandibular development, compound mutant mice, which are homozygous for both p27 deletion and the PTHrP1–84 knock-in mutation (p27−/−PthrpKI/KI), were generated. Their teeth and mandibular phenotypes were compared with those of p27−/−, PthrpKUK\ and wild-type mice. At 2 weeks of age, the mandibular mineral density, alveolar bone volume, osteoblast numbers, and dental volume, dentin sialoprotein-immunopo-sitive areas in the first molar were increased significantly in p27−/− mice and decreased dramatically in both PthrpKI/KI and p27−/− PthrpKI/KI mice compared with wild-type mice; however, these parameters were partly rescued in p27−/− PthrpKI/KI mice compared with PthrpKI/KI mice. These data demonstrate that the deletion of p27 in PthrpKI/KI mice can partially rescue defects in dental and mandibular development. Furthermore, we found that deletion of p27 in PthrpKI/KI mice partially corrected the dental and mandibular phenotype by modulating cell cyclin-regulating molecules and antioxidant enzymes. This study therefore indicates that the p27 pathway may function downstream in the action of PTHrP nuclear localization sequence to regulate dental and mandibular development. (Endocrinology 157: 1372–1384, 2016)

scholarly journals Analysis of mutations in the putative nuclear localization sequence of interleukin-1β

1991 ◽  
Vol 280 (1) ◽  
pp. 111-116 ◽  
Author(s):  
S Grenfell ◽  
N Smithers ◽  
S Witham ◽  
A Shaw ◽  
P Graber ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Interleukin 1 ◽  
Simian Virus 40 ◽  
T Antigen ◽  
Nuclear Accumulation ◽  
Nuclear Localization Sequence ◽  
Target Cells ◽  
Wild Type ◽  
Receptor Mediated Endocytosis ◽  
Localization Sequence

Previous studies have shown that, after receptor-mediated endocytosis, interleukin-1 alpha (IL1 alpha) and interleukin-1 beta (IL1 beta) are translocated to the nucleus, where they appear to accumulate. It has been suggested that nuclear translocation may be involved in the biological responsiveness of target cells to IL1 stimulation. The human IL1 beta molecule contains a seven-amino-acid sequence (-Pro208-Lys-Lys-Lys-Met-Glu-Lys-) that shows some sequence identity with the nuclear localization sequence of the simian-virus-40 large T-antigen. The effects of point mutations within this putative nuclear localization sequence on IL1 beta binding, receptor-mediated endocytosis and biological activity have been characterized. Mutants M49 (Lys210→Ala), M50 (Lys211→Ala) and M51 (Pro208→Ala) all retained the ability to bind to the IL1 receptor, albeit with lower affinity than the wild-type molecules. However, mutants M49, M50 and M51 showed greater biological potency than wild-type IL1 alpha or IL1 beta, as measured by the induction of IL2 secretion. However, receptor-mediated endocytosis and nuclear accumulation of M50 were comparable with those in the wild-type. These observations suggest that the putative nuclear localization sequence may play an important role in the generation of biological responses to IL1 stimulation, even though it may not influence internalization of the ligand.

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