Involvement of endogenous prostaglandin E2 in tubular epithelial regeneration through inhibition of apoptosis and epithelial-mesenchymal transition in cisplatin-induced rat renal lesions.
In the kidney, prostaglandin (PG) E2 is the main PG, playing important roles in maintaining homeostasis or development of pathological settings. Roles of PGE2 in renal lesions remain to be clarified. The expression patterns of PGE2 synthesis enzymes such as cyclooxygenase (COX)-1, COX-2 and microsomal PGE synthase (mPGES)-1, and PGE2 receptors (EP2 and EP4) were examined in cisplatin-induced rat renal failure. The immunoexpressions for COX-1, mPGES-1 and EP4 receptor were increased exclusively in the affected renal tubules, but those of COX-2 and EP2 receptor were not detected; increased expression of COX-1 was confirmed at mRNA level. Using rat renal epithelial cell line (NRK-52E), the effects of PGE2 on cell proliferation were investigated. The addition of PGE2 or 11-deoxy-PGE1 (EP4 receptor agonist) to NRK-52E increased the cell number, indicating the effects of PGE2 via EP4 receptor. Furthermore, 11-deoxy-PGE1-treated NRK-52E cells underwent the G0/G1 arrest and decreased apoptosis. NRK-52E treated with transforming growth factor (TGF)-beta1, an inducer of epithelial-mesenchymal transition (EMT), in the presence of 11-deoxy-PGE1 decreased the mRNA expression of alpha-smooth muscle actin (a marker of myofibroblasts). Collectively, the present study shows that COX-1 plays more important roles than dose COX-2 in cisplatin-induced rat renal failure; the product, PGE2, may regulate renal epithelial regeneration via EP4 receptor through inhibition of apoptosis and EMT.
Yamamoto
Emi
E
Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Izumisano-shi, Osaka, Japan.
Izawa
Takeshi
T
Juniantito
Vetnizah
V
Kuwamura
Mitsuru
M
Sugiura
Kikuya
K
Takeuchi
Tadayoshi
T
Yamate
Jyoji
J
D000527:Alprostadil / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D019746:Intramolecular Oxidoreductases; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D000071876:Prostaglandin-E Synthases; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000378:metabolism / Q000502:physiology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012038:Regeneration / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545646:Ptger2 protein, rat; C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053773:Transforming Growth Factor beta1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000527:Alprostadil; D015232:Dinoprostone; D002945:Cisplatin; C034008:11-deoxyprostaglandin E1