title: Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells.
abstract: We reported a functional incompetence in mesenchymal stem cells (MSCs) under uremia, but the mechanisms have not been explored. To study the mechanisms of dysfunctional MSCs induced by uremia, we characterized insulin signaling in MSCs and investigated the effect of uremic toxin, p-cresol, on the proangiogenic actions of insulin. In MSCs, insulin induced hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor, and stromal cell-derived factor 1α expressions via PI3K/Akt-dependent pathway. MSCs treated with p-cresol exhibited altered insulin signaling in a selective manner for insulin receptor substrate-1/PI3K/Akt pathway, whereas ERK pathway remained active. The insulin-induced increase of HIF-1α was blunted by p-cresol treatment. This Akt-selective insulin resistance was also observed in MSCs isolated from chronic kidney disease (CKD) mice. In mice model of hindlimb ischemia, blood flow recovery, capillary density, and local production of angiogenic factors in the ischemic limb treated with CKD MSCs were significantly inferior to those promoted by control MSCs. However, modifying CKD MSCs by overexpression of HIF-1α restored all of these changes. Taken together, these data suggest that p-cresol contributes to insulin resistance in a selective manner for Akt pathway. This might be a biological explanation for the functional incompetence of MSCs under uremia through defects in the insulin-induced elevation of HIF-1α protein expression.
authors.affiliation: Department of Internal Medicine, Soon Chun Hyang University, Seoul, Korea; Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Noh
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Yu
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Jang
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Hwang
authors.forename: Jin Seok
authors.initials: JS
authors.lastname: Jeon
authors.forename: Soon Hyo
authors.initials: SH
authors.lastname: Kwon
authors.forename: Dong Cheol
authors.initials: DC
authors.lastname: Han
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003408:Cresols / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014511:Uremia / Q000378:metabolism / Q000473:pathology*
chemical_list: D003408:Cresols; C032538:4-cresol; D051057:Proto-Oncogene Proteins c-akt
keywords: Chronic kidney disease; Insulin resistance; Mesenchymal stem cells; p-Cresol