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Activation of renal signaling pathways in db/db mice with type 2 diabetes
D Feliers1, S Duraisamy, J L Faulkner
1Department of Medicine, University of Texas Health Science Center at San Antonio, 78229-3900, USA.
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 beta chain of the insulin receptor was increased nearly fourfold (P < 0.0235). Additionally, the kinase activity of the immunoprecipitated insulin receptor beta 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.
Insights
Signaling pathways in the kidney are altered in type 2 diabetes. This study shows increased insulin receptor activity in diabetic nephropathy, suggesting a key role in disease development.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Altered signaling pathway regulation is implicated in renal disease pathogenesis.
- Type 2 diabetes is associated with significant renal complications, including diabetic nephropathy.
Purpose of the Study:
- To investigate renal cortical signaling pathways in the early stages of type 2 diabetic nephropathy.
- To determine the role of insulin receptor signaling in diabetic kidney disease.
Main Methods:
- Examined renal cortical signaling pathways in control and db/db mice (type 2 diabetes model).
- Assessed tyrosine phosphorylation, phosphatidylinositol 3-kinase (PI 3-kinase), Akt (PKB), and ERK1/2-type mitogen-activated protein (MAP) kinase activities.
- Investigated insulin receptor activation and associated PI 3-kinase activity.
Main Results:
- Diabetic mice exhibited increased tyrosine phosphorylation of renal cortical proteins.
- Significantly augmented renal cortical activities of PI 3-kinase, Akt, and ERK1/2-type MAP kinase were observed.
- Increased PI 3-kinase activity was partly due to enhanced insulin receptor activation, with elevated insulin receptor kinase activity and tyrosine phosphorylation.
Conclusions:
- Receptor signaling pathways are activated in the renal cortex of type 2 diabetic mice.
- Augmented insulin receptor activity plays a potential role in the development of type 2 diabetic nephropathy.