title: Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation.
abstract: Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.
authors.affiliation: Department of Pediatrics, Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, 84101, Israel. ldaniel@bgu.ac.il.
authors.forename: Daniel
authors.initials: D
authors.lastname: Landau
authors.forename: Renanah
authors.initials: R
authors.lastname: Eshet
authors.forename: Ariel
authors.initials: A
authors.lastname: Troib
authors.forename: Yotam
authors.initials: Y
authors.lastname: Gurman
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Ralph
authors.initials: R
authors.lastname: Rabkin
authors.forename: Yael
authors.initials: Y
authors.lastname: Segev
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491409:Socs2 protein, mouse; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D013006:Growth Hormone; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017526:Receptor, IGF Type 1; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases