TY - JOUR
T1 - Activation of renal signaling pathways in db/db mice with type 2 diabetes
AU - Feliers, Denis
AU - Duraisamy, Senthil
AU - Faulkner, Jennifer L.
AU - Duch, John
AU - Lee, Adrian V.
AU - Abboud, Hanna E.
AU - Choudhury, Goutam Ghosh
AU - Kasinath, Balakuntalam S.
N1 - Funding Information:
These studies were supported by the Veterans' Administration Research Service Merit Award and Research Enhancement Award Program (B.S.K., G.G.C., H.E.A.), the National Kidney Foundation of South Texas (B.S.K.), the American Diabetes Association (B.S.K.), and the National Institutes of Health (GGC DK50190, HEA DK43988). A.V.L. is a recipient of Susan G. Komen Breast Cancer Foundation Award. Preliminary findings contained in this manuscript were presented as abstracts in the annual meetings of the American Society of Nephrology (1999) and the American Diabetes Association (2000).
PY - 2001
Y1 - 2001
N2 - Background. Altered regulation of signaling pathways may contribute to the pathogenesis of renal disease. We examined renal cortical signaling pathways in type 2 diabetes. Methods. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in the early phase of diabetic nephropathy associated with renal matrix expansion and albuminuria. Results. Tyrosine phosphorylation of renal cortical proteins was increased in diabetic mice. Renal cortical activities of phosphatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates, Akt (PKB), and ERK1/2-type mitogen-activated protein (MAP) kinase activities were significantly augmented sixfold (P < 0.01), twofold (P < 0.0003), and sevenfold (P < 0.001), respectively, in diabetic mice compared with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation, as PI 3-kinase activity associated with β chain of the insulin receptor was increased nearly fourfold (P < 0.0235). Additionally, the kinase activity of the immunoprecipitated insulin receptor β chain was augmented in the diabetic renal cortex, and tyrosine phosphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunoprecipitates and Akt also were increased threefold (P < 0.05) and twofold (P < 0.0002), respectively. However, there was no change in the hepatic insulin receptor-associated PI 3-kinase activity. Additionally, the hepatic ERK1/2-type MAP kinase activity was inhibited by nearly 50% (P < 0.01). Conclusions. These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, and suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes.
AB - Background. Altered regulation of signaling pathways may contribute to the pathogenesis of renal disease. We examined renal cortical signaling pathways in type 2 diabetes. Methods. The status of renal cortical signaling pathways was examined in control and db/db mice with type 2 diabetes in the early phase of diabetic nephropathy associated with renal matrix expansion and albuminuria. Results. Tyrosine phosphorylation of renal cortical proteins was increased in diabetic mice. Renal cortical activities of phosphatidylinositol 3-kinase (PI 3-kinase) in antiphosphotyrosine immunoprecipitates, Akt (PKB), and ERK1/2-type mitogen-activated protein (MAP) kinase activities were significantly augmented sixfold (P < 0.01), twofold (P < 0.0003), and sevenfold (P < 0.001), respectively, in diabetic mice compared with controls. A part of the increased renal cortical PI 3-kinase activity was due to insulin receptor activation, as PI 3-kinase activity associated with β chain of the insulin receptor was increased nearly fourfold (P < 0.0235). Additionally, the kinase activity of the immunoprecipitated insulin receptor β chain was augmented in the diabetic renal cortex, and tyrosine phosphorylation of the insulin receptor was increased. In the liver, activities of PI 3-kinase in the antiphosphotyrosine immunoprecipitates and Akt also were increased threefold (P < 0.05) and twofold (P < 0.0002), respectively. However, there was no change in the hepatic insulin receptor-associated PI 3-kinase activity. Additionally, the hepatic ERK1/2-type MAP kinase activity was inhibited by nearly 50% (P < 0.01). Conclusions. These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, and suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes.
KW - Akt
KW - Diabetic nephropathy
KW - Insulin receptor
KW - MAP kinase
KW - Phosphotidylinositol 3-kinase
KW - Receptor signaling
KW - Renal cortex
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U2 - 10.1046/j.1523-1755.2001.060002495.x
DO - 10.1046/j.1523-1755.2001.060002495.x
M3 - Article
C2 - 11473632
AN - SCOPUS:0034924522
SN - 0085-2538
VL - 60
SP - 495
EP - 504
JO - Kidney International
JF - Kidney International
IS - 2
ER -