TY - JOUR
T1 - Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation
AU - Landau, Daniel
AU - Eshet, Renanah
AU - Troib, Ariel
AU - Gurman, Yotam
AU - Chen, Yu
AU - Rabkin, Ralph
AU - Segev, Yael
N1 - Funding Information:
Acknowledgments This study was supported by a Grant-in-aid of the US-Israel Binational Science foundation (no. 2003055) to DL, RR, and YS, and a National Institute of Health Grant RO1 DK 068517 and a Merit Review Grant from the Research Service of the US Department Veterans Affairs to RR.
PY - 2009/1/1
Y1 - 2009/1/1
N2 - 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.
AB - 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.
KW - Diabetic nephropathy
KW - Growth hormone receptor
KW - JAK2
KW - Phosphorylation
KW - STAT5
UR - http://www.scopus.com/inward/record.url?scp=70349576333&partnerID=8YFLogxK
U2 - 10.1007/s12020-009-9190-2
DO - 10.1007/s12020-009-9190-2
M3 - Article
AN - SCOPUS:70349576333
SN - 1355-008X
VL - 36
SP - 126
EP - 134
JO - Endocrine
JF - Endocrine
IS - 1
ER -
