title: Insulin-like growth factor-1 (IGF-1) inhibits the basolateral Cl channels in the thick ascending limb of the rat kidney.
abstract: The aim of the present study is to test the hypothesis that insulin-like-growth factor-1 (IGF-1) plays a role in the regulation of basolateral Cl channels in the thick ascending limb (TAL). The patch-clamp experiments demonstrated that application of IGF-I or insulin inhibited the basolateral 10-pS Cl channels. However, the concentration of insulin required for the inhibition of the Cl channels by 50% (K(1/2)) was ten times higher than those of IGF-1. The inhibitory effect of IGF-I on the 10-pS Cl channels was blocked by suppressing protein tyrosine kinase or by blocking phosphoinositide 3-kinase (PI3K). In contrast, inhibition of phospholipase C (PLC) failed to abolish the inhibitory effect of IGF-1 on the Cl channels in the TAL. Western blot analysis demonstrated that IGF-1 significantly increased the phosphorylation of phospholipid-dependent kinase (PDK) at serine residue 241 (Ser(241)) and AKT at Ser(473) in the isolated medullary TAL. Moreover, inhibition of PI3K with LY294002 abolished the effect of IGF-1 on the phosphorylation of PDK and AKT. The notion that the effect of IGF-1 on the 10-pS Cl channels was induced by stimulation of PDK-AKT-mTOR pathway was further suggested by the finding that rapamycin completely abolished the effect of IGF-1 on the 10-pS Cl channels in the TAL. We conclude that IGF-1 inhibits the basolateral Cl channels by activating PI3K-AKT-mTOR pathways. The inhibitory effect of IGF-1 on the Cl channels may play a role in ameliorating the ischemia-induced renal injury through IGF-1 administration.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin 150086, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Wennan
authors.initials: W
authors.lastname: Li
authors.forename: Shumin
authors.initials: S
authors.lastname: Kong
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Gu
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Wang
authors.forename: WenHui
authors.initials: W
authors.lastname: Wang
authors.forename: Ruimin
authors.initials: R
authors.lastname: Gu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018118:Chloride Channels / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D005260:Female; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008138:Loop of Henle / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018118:Chloride Channels; D002867:Chromones; D007328:Insulin; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007334:Insulin-Like Growth Factor I