Beraprost sodium, an analogue of prostacyclin, induces the expression of mitogen-activated protein kinase phosphatase and inhibits the proliferation of cultured mesangial cells

Togawa, Masaki; Haneda, Masakazu; Araki, Shin‐ichi; Sugimoto, Toshiro; Isono, Motohide; Hidaka, Hideki; Yasuda, Hitoshi; Kashiwagi, Atsunori; Kikkawa, Ryuichi

doi:10.1016/s0014-2999(97)01208-9

Cited by 24 publications

(10 citation statements)

References 9 publications

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“…This effect, however, seems to be cell type dependent and may vary depending on the PGI 2 analog in question. For example, our work indicates that CCP decreases p27 levels in rat mesangial cells (88) with no change in thymidine incorporation, but Togawa et al (124) did show an inhibitory effect of beraprost sodium on rat mesangial cell proliferation that is mediated by induction of mitogen-activated protein kinase phosphatase (MKP-1), which inhibits the MAPK pathway. Furthermore, in a murine carcinoma cell line using another PGI 2 analog (carba-PGI 2 ) no effect on cellular proliferation or thymidine incorporation was noted (7).…”

Section: Pgi 2 and Renal Growthmentioning

confidence: 56%

Prostacyclin signaling in the kidney: implications for health and disease

Nasrallah

Hébert

2005

American Journal of Physiology-Renal Physiology

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The balance between vasodilator and vasoconstrictor pathways is key to the maintenance of homeostasis and the outcome of disease. In the kidney, prostaglandins (PGs) uphold this balance and regulate renal function: hemodynamics, renin secretion, growth responses, tubular transport processes, and cell fate. With the advent of cyclooxygenase (COX)-2-selective inhibitors, targeted deletions in mice (COX knockouts, PG receptor knockouts), and the discovery of intracrine signaling options for PGs (peroxisome proliferator-activated receptors and perinuclear PGE(2) receptors: EP(1,3,4)), many advances have been made in the study of arachidonic acid metabolites. Although prostacyclin (PGI(2)) is a major product of the COX pathway, there is very little emphasis on its importance to the kidney. This review will discuss PGI(2) biology and its relevance to different aspects of renal disease (growth, fibrosis, apoptosis), highlighting the most significant research from the past decade of PGI(2) literature, what we have learned from other organ systems, while stressing the significance of cross talk between various PGI(2) signaling pathways and its implications for renal health and disease.

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Section: Pgi 2 and Renal Growthmentioning

confidence: 56%

Prostacyclin signaling in the kidney: implications for health and disease

Nasrallah

Hébert

2005

American Journal of Physiology-Renal Physiology

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“…We also demonstrated that treatment with the selective COX-2 inhibitor NS398 reduces glomerular hypertrophy in uninephrectomized rats [8]. Although prostaglandins are known to affect cell growth [9, 10], their effects on regulators of the cell cycle has not been well-characterized in the kidney. In the present study, we therefore hypothesized that the major COX-2 product PGE 2 causes mesangial cell hypertrophy in vitro via alterations in cell cycle regulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

PGE<sub>2</sub> Causes Mesangial Cell Hypertrophy and Decreases Expression of Cyclin D3

et al. 2009

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Background/Aims: Glomerular hypertrophy is a feature of many glomerular diseases and is associated with the development of renal failure. We previously demonstrated that the cyclooxygenase 2 inhibitor, NS398, reduced glomerular size after uninephrectomy. Thus, we hypothesized that prostaglandin (PG) E₂ would cause mesangial cell hypertrophy in vitro. Methods: We used a mesangial cell line and primary culture of rat mesangial cells. The effects of PGE₂ on mesangial cell hypertrophy were determined using immunohistochemistry and image analysis to assess cell size, 3H-leucine incorporation as a measure of protein synthesis and flow cytometry to assess cell cycle status. Western blot was used to examine the effect of PGE₂ on expression of cyclin D3, p15, p27 and cyclin-dependent kinase 4 – known regulators of the cell cycle. Results: PGE₂ increased cell size by 13% and protein synthesis (3H-leucine incorporation) by 35% over 24 h. By flow cytometry, PGE₂ increased the percentage of cells in G0/G1 phase of the cell cycle from 70.13 ± 1.01 to 74.06 ± 1.18% and conversely, decreased the number of cells in S phase from 24.07 ± 1.06 to 22.03 ± 0.78%. The number of cells in G2/M was also reduced. Expression of cyclin D3 was decreased by 60% after treatment with PGE₂, while expression of p27 was increased. The effects of PGE₂ on cell size and flow cytometry were reproduced by the prostaglandin E₂ receptors EP1/EP3 agonist sulprostone. Conclusion: PGE₂ induces mesangial cell hypertrophy and cell cycle arrest via its EP1 receptor.

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“…51 Since the agents which increase cellular cAMP are known to inhibit MC proliferation, Togawa et al examined the effects of beraprost (34) on MC proliferation. 52,53 Beraprost (34) significantly inhibited FCS-stimulated MC proliferation in concentrations enough to increase cellular cAMP (0.1-1 mM). By Northern blot analysis, beraprost (34) induced the expression of MKP-1, a MAPK phosphatase, in a dose-and timedependent manner.…”

Section: O T H E R M E C H a N I S Mmentioning

confidence: 99%

Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease

Kurogi

2002

Medicinal Research Reviews

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Mesangial cells (MC) serve a number of functions in the renal glomerular capillary including structural support of the capillary tuft, modulation of glomerular hemodynamics, and a phagocytic function allowing removal of macromolecules and immune complexes. The proliferation of MC is a prominent feature of glomerular disease including IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy. In experimental animal models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix in the mesangium and glomerulosclerosis. Reduction of MC proliferation in glomerular disease models by treatment with heparin, low-protein diet, or antibodies to platelet-derived growth factor (PDGF), have been shown to reduce extracellular matrix expansion and glomerulosclerotic changes. Therefore, MC proliferation inhibitors may offer therapeutic opportunities for the treatment of proliferative glomerular disease. It is also known that the MC proliferation is inhibited by many kinds of pharmacological drugs, for example, angiotensin converting enzyme (ACE) inhibitors, leukotriene D(4) (LTD(4)) antagonists, PDGF inhibitors, matrix metalloproteinases (MMP) inhibitors, 3-hydroxy-3 methyl glutaryl-coenzymeA (HMG-CoA) inhibitors, cyclin-dependent kinases (CDK) inhibitors, and others. This review summarizes the recently reported MC proliferation inhibitors with their pharmacological properties on the basis of their chemical structures.

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Beraprost sodium, an analogue of prostacyclin, induces the expression of mitogen-activated protein kinase phosphatase and inhibits the proliferation of cultured mesangial cells

Cited by 24 publications

References 9 publications

Prostacyclin signaling in the kidney: implications for health and disease

Prostacyclin signaling in the kidney: implications for health and disease

PGE<sub>2</sub> Causes Mesangial Cell Hypertrophy and Decreases Expression of Cyclin D3

Mesangial cell proliferation inhibitors for the treatment of proliferative glomerular disease

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