Modulation of Growth Hormone Signal Transduction in Kidneys of Streptozotocin-Induced Diabetic Animals

Modulation of Growth Hormone Signal Transduction in Kidneys of Streptozotocin-Induced Diabetic Animals Effect of a Growth Hormone Receptor Antagonist Ana C.P. Thirone , John A. Scarlett , Alessandra L. Gasparetti , Eliana P. Araujo , Maria H.L. Lima , Carla R.O. Carvalho , Lício A. Velloso and Mario J.A. Saad From the Department of Internal Medicine, FCM, University Of Campinas, Campinas, Sao Paulo, Brazil Abstract 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. Footnotes Address correspondence and reprint requests to Mario J.A. Saad, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13081-970, Campinas, SP Brasil. E-mail: msaad{at}fcm.unicamp.br . Received for publication 1 December 2000 and accepted in revised form 9 April 2002. J.A.S. is an employee, an officer, and a director for and holds stock in Sensus Drug Development Corporation. DAG, diacylglycerol; GH, growth hormone; GHR, growth hormone receptor; Grb2, growth factor receptor bound 2; IRS, insulin receptor substrate; MAP, mitogen-activated protein; PKB, protein kinase B; PKC, protein kinase 3;