Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells: Implications for diabetic nephropathy

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar biological effects through the PTH/PTHrP receptor. Because PTHrP exhibits vasodilatory properties, we evaluated the hypothesis that this hormone interacts with human mesangial cells (HMC). The PTHrP prevented both the expected reduction in the planar cell surface area and the increase in myosin light-chain phosphorylation induced by platelet-activating factor (PAF) on HMC, in a dose-dependent manner. This effect was completely blocked by pertussis toxin and dideoxyadenosine, suggesting that a G protein-coupled receptor and cAMP are important in the PTHrP transduction mechanism. Moreover, PTHrP increased cAMP synthesis and thymidine incorporation in HMC. However, whereas RT-PCR and Southern and Northern blot analyses demonstrated the expression of human PTH/PTHrP receptor in human kidney cortex, no expression could be demonstrated in HMC. These results show that PTH and PTHrP directly interact with mesangial cells. These effects might be mediated by a receptor different from the PTH/PTHrP receptor.

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

Bioscience Reports ◽

10.1042/bsr20182293 ◽

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.

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Novel Role of Parathyroid Hormone-Related Protein in the Pathophysiology of the Diabetic Kidney: Evidence from Experimental and Human Diabetic Nephropathy

Journal of Diabetes Research ◽

10.1155/2013/162846 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Montserrat Romero ◽

Arantxa Ortega ◽

Nuria Olea ◽

María Isabel Arenas ◽

Adriana Izquierdo ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Parathyroid Hormone ◽

Renal Injury ◽

Renal Diseases ◽

Protective Effects ◽

Ang Ii ◽

Related Protein ◽

Renal Hypertrophy ◽

Glomerular Diseases ◽

Parathyroid Hormone Related Protein

Parathyroid hormone-related protein (PTHrP) and its receptor type 1 (PTH1R) are extensively expressed in the kidney, where they are able to modulate renal function. Renal PTHrP is known to be overexpressed in acute renal injury. Recently, we hypothesized that PTHrP involvement in the mechanisms of renal injury might not be limited to conditions with predominant damage of the renal tubulointerstitium and might be extended to glomerular diseases, such as diabetic nephropathy (DN). In experimental DN, the overexpression of both PTHrP and the PTH1R contributes to the development of renal hypertrophy as well as proteinuria. More recent data have shown, for the first time, that PTHrP is upregulated in the kidney from patients with DN. Collectively, animal and human studies have shown that PTHrP acts as an important mediator of diabetic renal cell hypertrophy by a mechanism which involves the modulation of cell cycle regulatory proteins and TGF-β1. Furthermore, angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be responsible for PTHrP upregulation in these conditions. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches.

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

Endocrinology ◽

10.1210/en.2012-1802 ◽

2013 ◽

Vol 154 (2) ◽

pp. 853-864 ◽

Cited By ~ 24

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.

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Parathyroid hormone-related protein induces hypertrophy in podocytes via TGF- 1 and p27Kip1: implications for diabetic nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfq104 ◽

2010 ◽

Vol 25 (8) ◽

pp. 2447-2457 ◽

Cited By ~ 14

Author(s):

M. Romero ◽

A. Ortega ◽

A. Izquierdo ◽

P. Lopez-Luna ◽

R. J. Bosch

Keyword(s):

Diabetic Nephropathy ◽

Parathyroid Hormone ◽

Related Protein ◽

Parathyroid Hormone Related Protein

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The effect of nitro-oleic versus losartan in diabetic nephropathy: modulation of parathyroid hormone related protein

Folia Morphologica ◽

10.5603/fm.a2018.0057 ◽

2015 ◽

Author(s):

Asmaa Mohammed ◽

Nermeen Sadek ◽

Mohamed Eshra ◽

Effat Khowailed ◽

Laila Rashed ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Parathyroid Hormone ◽

Related Protein ◽

Parathyroid Hormone Related Protein

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Faculty Opinions recommendation of The parathyroid hormone-related protein system and diabetic nephropathy outcome in streptozotocin-induced diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14433.471935 ◽

2006 ◽

Author(s):

Roland Blantz

Keyword(s):

Diabetic Nephropathy ◽

Parathyroid Hormone ◽

Related Protein ◽

Protein System ◽

Parathyroid Hormone Related Protein ◽

Streptozotocin Induced Diabetes

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Dual roles of parathyroid hormone related protein in TGF-β1 signaling and fibronectin up-regulation in mesangial cells

Bioscience Reports ◽

10.1042/bsr20171061 ◽

2017 ◽

Vol 37 (5) ◽

Cited By ~ 4

Author(s):

Su-Zhen Wu ◽

Si-Jun Yang ◽

Hong-Min Chen ◽

Fang-Fang Peng ◽

Hong Yu ◽

...

Keyword(s):

Parathyroid Hormone ◽

Mesangial Cells ◽

Inhibitory Effect ◽

Related Protein ◽

Dual Roles ◽

Protein Levels ◽

Parathyroid Hormone Related Protein ◽

Pthrp Receptor ◽

First Time ◽

Tgf Β1

Little is known about the cross-talk between parathyroid hormone (PTH) related protein (PTHrP) and TGF-β1 in mesangial cells (MCs). Our results showed that PTHrP treatment (≤3 h) induced internalization of PTH1R (PTH/PTHrP receptor)–TβRII (TGF-β type 2 receptor) complex and suppressed TGF-β1-mediated Smad2/3 activation and fibronectin (FN) up-regulation. However, prolonged PTHrP treatment (12–48 h) failed to induce PTH1R–TβRII association and internalization. Total protein levels of PTH1R and TβRII were unaffected by PTHrP treatment. These results suggest that internalization of PTH1R and TβRII after short PTHrP treatment might not lead to their proteolytic destruction, allowing the receptors to be recycled back to the plasma membrane during prolonged PTHrP exposure. Receptor re-expression at the cell surface allows PTHrP to switch from its initial inhibitory effect to promote induction of FN. Our study thus demonstrates the dual roles of PTHrP on TGF-β1 signaling and FN up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for diabetic kidney disease (DKD).

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