Modulation of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist.
Growth hormone (GH) and IGFs have a long distinguished history in diabetes, with possible participation in the development of renal complications. The implicated effect of GH in diabetic end-stage organ damage may be mediated by growth hormone receptor (GHR) or postreceptor events in GH signal transduction. The present study investigates the effects of diabetes induced by streptozotocin (STZ) on renal GH signaling. Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. Immunohistochemical studies show that GH-induced p-Akt and p-ERK activation is apparently more pronounced in the kidneys of diabetic rats. Administration of G120K-PEG, a GH antagonist, in diabetic mice shows inhibitory effects on diabetic renal enlargement and reverses the alterations in GH signal transduction observed in diabetic animals. The present study demonstrates a role for GH signaling in the pathogenesis of early diabetic renal changes and suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.
Thirone
Ana C P
AC
Department of Internal Medicine, FCM, State University Of Campinas, 13080-970 Campinas, Sao Paulo, Brazil.
Scarlett
John A
JA
Gasparetti
Alessandra L
AL
Araujo
Eliana P
EP
Lima
Maria H L
MH
Carvalho
Carla R O
CR
Velloso
Lício A
LA
Saad
Mario J A
MJ
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D051380:GRB2 Adaptor Protein; D013006:Growth Hormone / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D053614:Janus Kinase 2; D007668:Kidney / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009929:Organ Size; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017208:Rats, Wistar; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors*; D012016:Reference Values; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001786:Blood Glucose; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2