Altered growth response to prostaglandin E2 and its receptor signaling in mesangial cells from stroke-prone spontaneously hypertensive rats.
OBJECTIVE
Prostaglandin (PG) E2, a major arachidonic acid metabolite in the kidney, acts on four receptor subtypes (EP1, EP2, EP3 and EP4). One of major causes of end-stage renal failure is hypertensive renal disease, in which enhanced renal PGE2 production has been shown. In this study, to explore the pathophysiological significance of EP subtypes in the kidney, we examined the role of EP subtypes on proliferation of mesangial cells (MCs) from stroke-prone spontaneously hypertensive rats (SHRSPs), which show faster growth than those from normotensive Wistar-Kyoto rats (WKYs).


METHODS
Using MCs from SHRSPs and WKYs, we investigated DNA synthesis and its upstream event, the phosphorylation of extracellular signal-regulated kinase (ERK), together with the gene expression of EP subtypes.


RESULTS
Sulprostone, an EP1 agonist, dose-dependently increased DNA synthesis and the phosphorylation of ERK in MCs from both strains. The EP4 agonist, 11-deoxy-PGE1, inhibited sulprostone-induced phosphorylation of ERK in WKY-MCs. In contrast, 11-deoxy-PGE1 failed to inhibit the ERK activity in SHRSP-MCs. Interestingly, cAMP production mediated by EP4 was markedly attenuated in SHRSP-MCs as compared with that in WKY-MCs, despite the overproduction of endogenous PGE2 in SHRSP-MCs. Similar gene expressions of EP1 and EP4 and only faint expression of EP3 were detected in MCs from both strains.


CONCLUSIONS
These results indicate that the PGE2/EP4 system counteracts the PGE2/EP1 system at the level of the intracellular signaling pathway. The altered EP4 signaling may play a critical role in the exaggerated mesangial growth in SHRSPs.
Suganami
T
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Tanaka
I
I
Mukoyama
M
M
Kotani
M
M
Muro
S
S
Mori
K
K
Goto
M
M
Ishibashi
R
R
Kasahara
M
M
Yahata
K
K
Makino
H
H
Sugawara
A
A
Nakao
K
K
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D004247:DNA / Q000096:biosynthesis; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000187:drug effects / Q000503:physiopathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020239:Receptor Cross-Talk; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000145:classification / Q000235:genetics / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction
D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; C016767:sulprostone; D004247:DNA; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone