Involvement of endogenous prostaglandin E2 in tubular epithelial regeneration through inhibition of apoptosis and epithelial-mesenchymal transition in cisplatin-induced rat renal lesions
Emi Yamamoto1, Takeshi Izawa1, Vetnizah Juniantito1, Mitsuru Kuwamura1, Kikuya Sugiura2, Tadayoshi Takeuchi3 and Jyoji Yamate1
Laboratories of 1Veterinary Pathology, 2Cell Pathobiology and 3Veterinary Pharmacology, Life and Environmental Sciences, Osaka Prefecture University, Izumisano-shi, Osaka, Japan.
Offprint requests to: Jyoji Yamate, Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano-shi, Osaka, 598-8531. e-mail: firstname.lastname@example.org
Summary. 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)-ß1, an inducer of epithelial-mesenchymal transition (EMT), in the presence of 11-deoxy-PGE1 decreased the mRNA expression of α-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. Histol Histopathol 25, 995-1007 (2010)
Key words: Cisplatin, Cyclooxygenase-1, PGE2, Rat, Renal tubular regeneration