title: P-gp-induced modulation of regulatory volume increase occurs via PKC in mouse proximal tubule.
abstract: The present study examined the role of protein kinase C (PKC) in the P-glycoprotein (P-gp)-induced modulation of regulatory volume increase (RVI) in the isolated nonperfused proximal tubule S2 segments from mice lacking both mdr1a and mdr1b genes (KO) and wild-type (WT) mice. The hyperosmotic solution (500 mosmol/kgH(2)O) involving 200 mM mannitol activated PKC and elicited RVI in the tubules from KO mice but not from WT mice. The addition of the hyperosmotic solution including the PKC activator phorbol 12-myristate 13-acetate (PMA) to the tubules of the WT mice activated PKC and elicited RVI. The hyperosmotic solution in the presence of the P-gp inhibitors (verapamil or cyclosporin A) elicited RVI in the tubules from the WT mice but not from the KO mice. The PMA- and the P-gp inhibitors-induced RVI was abolished by cotreatment with the PKC inhibitors (staurosporine or calphostin C). In the tubules of the KO mice, the PKC inhibitors abolished RVI, but PMA did not. In the tubules of the WT mice, the microtubule disruptor (colchicine), the microfilament disruptor (cytochalasin B), the phosphatidylinositol 3-kinase (PI 3-kinase) blocker (wortmannin), but not another PI 3-kinase blocker (LY-294002), inhibited the PMA-induced RVI. In the tubules of the KO mice, colchicine, cytochalsin B, and wortmannin abolished RVI, but LY-294002 did not. We conclude that 1) in the mouse proximal tubule, P-gp-induced modulation of RVI occurs via PKC; and 2) the microtubule, microfilament, and wortmannin-sensitive, LY-294002-insensitive PI 3-kinase contribute to the PKC-induced RVI.
authors.affiliation: Department of Nephrology, Jichi Medical School, Tochigi, 329-0498 Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Miyata
authors.forename: Koji
authors.initials: K
authors.lastname: Okada
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Asano
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D008841:Actin Cytoskeleton / Q000502:physiology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D004234:Diuretics, Osmotic / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006982:Hypertonic Solutions / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D000077191:Wortmannin; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000730:Androstadienes; D002121:Calcium Channel Blockers; D002273:Carcinogens; D002867:Chromones; D003078:Colchicine; D016572:Cyclosporine; D003571:Cytochalasin B; D004234:Diuretics, Osmotic; D004791:Enzyme Inhibitors; D006982:Hypertonic Solutions; D008353:Mannitol; D009025:Morpholines; D009281:Naphthalenes; D010704:Phorbols; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D014700:Verapamil; D000077191:Wortmannin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C095122:multidrug resistance protein 3; C058819:calphostin C; C033085:phorbol