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Submitted on September 19, 2006
Accepted on January 23, 2007
Pediatrics & Communicable Diseases, Internal Medicine, Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, Department of Biological Sciences, University of Toledo, Academic and Children's Renal Unit, University of Bristol, U.K., Edison Biotechnology Institute, and Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, and InternalMedicine, University of Alabama, Birmingham, AL
* To whom correspondence should be addressed. E-mail: rammenon{at}umich.edu.
Growth hormone (GH) excess in both the human and in transgenic animal models is characterized by significant changes in blood pressure and renal function. The GH/GH receptor (GHR) axis is also implicated in the development of diabetic nephropathy. However it is not clear if GH's actions on renal function are due to indirect actions mediated via changes in blood pressure and vascular tone or due to direct action of GH on the kidney. We hypothesized that functional GHRs are expressed on the glomerular podocyte enabling direct actions of GH on glomerular function. Real-time PCR, immunohistochemistry, and Western blot analysis of murine podocyte cells (MPC-5) and kidney glomeruli demonstrated expression of GHR mRNA and protein. Exposure of both murine and human podocytes to GH (50-500 ng/ml) resulted in an increase in abundance of phosphorylated STAT5, JAK2 and ERK1/2 proteins. Exposure of podocytes to GH also caused changes in the intracellular distribution of the JAK2 adapter protein SH2-B
, stimulation of focal adhesion kinase, increase in reactive oxygen species (ROS), and GH-dependent changes in the actin cytoskeleton, We conclude that glomerular podocytes express functional GHRs and that GH increases levels of ROS and induces reorganization of the actin cytoskeleton in these cells. These results provide a novel mechanistic link between GH's actions and glomerular dysfunction in disorders such as acromegaly and diabetic glomerulosclerosis.
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