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Urotensin II is an Autocrine/Paracrine Growth Factor for the Porcine Renal Epithelial Cell Line, LLCPK1

Department of Clinical and Molecular Endocrinology (M.M., M.S., N.F., N.O., T.Y., Y.H.), Tokyo Medical and Dental University Graduate School, Tokyo, 113-8519, Japan; and Second Department of Internal Medicine (N.T.), University of Ryukyus, Okinawa 903-0215, Japan

Address all correspondence and requests for reprints to: Yukio Hirata, M.D., Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: yhirata.cme{at}tmd.ac.jp.

Urotensin-II (UII), a cyclic dodecapeptide with potent cardiovascular effects, has recently been shown to be abundantly expressed in the human kidney and excreted in human urine. To investigate whether UII acts as an autocrine/paracrine growth factor for renal epithelial cells, we have studied the effects of human UII (hUII) on DNA synthesis, cytosolic free Ca²⁺ concentration ([Ca²⁺]_i), ERK activation, and protooncogene (c-myc) expression in a porcine renal epithelial cell line (LLCPK1). hUII stimulated [³H]thymidine uptake into quiescent cells in a dose-dependent manner (10^-9 to 10^-7 M); this effect was inhibited by a protein kinase C inhibitor (GF109203X), a MAPK kinase inhibitor (PD98059), and a calcium channel blocker (nicardipine). Neither phosphatidyl inositol-3 kinase inhibitors (LY294002, wortmannin) nor p38 kinase inhibitor (SB203580) affected the hUII-induced DNA syntheses. hUII rapidly (within 5 min) and dose-dependently (10^-9 to 10^-7 M) increased [Ca²⁺]_i in fura-2-loaded cells. hUII also caused a rapid and transient activation of ERK1/2 and induction of c-myc. LLCPK1 cells expressed UII mRNA and its receptor GPR14 mRNA, as determined by RT-PCR, and released UII-like immunoreactivity into media. Neutralization of endogenous UII by anti-hUII antibody, but not nonimmune serum, significantly suppressed DNA synthesis. These data suggest that hUII is an autocrine/paracrine growth factor for renal epithelial cells via activation of both protein kinase C and ERK1/2 pathways as well as Ca²⁺ influx via voltage-dependent Ca²⁺ channels.

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