Expression and function of the growth hormone receptor (GHR) is essential for the action of pituitary growth hormone (GH). The GH/IGF-1 axis plays a critical permissive role in the pathogenesis of chronic microvascular complications of DM. A direct role for GH/GHR in the pathogenesis of DM nephropathy is supported by studies using GH and GH-antagonist transgenic mice, total GHR knockout mice, and pharmacological blockade of GHR using pegvisomant. These studies demonstrate that absence of functional GHR confers a protective effect against DM nephropathy. Our laboratory is focused on understanding the molecular and cellular basis for GH's actions in the pathogenesis of DM nephropathy and the identification of novel therapeutic targets that will alter the outcome of diabetic kidney disease. Our recent studies have established the molecular mechanisms resulting in dysregulation of the GHR gene in DM. We have identified fatty acids (FA) as a specific metabolic signal that transduces the effect of DM on GHR gene expression and have identified the glomerular podocyte as potential target of GH action in the kidney. We propose to expand on these preliminary observations by the pursuing the following SPECIFIC AIMS:
Specific Aim 1 tests the hypothesis that FAs modulate the expression of the GHR gene expression in DM in a tissue-specific manner. The proposed experimental paradigm will identify and characterize a potentially novel trans-acting factor(s) that plays a role in the transduction of the effect of FA on GHR expression. We also propose to test the sub- hypothesis that FAs transduce their effects on GHR expression via Toll receptors and increase in oxidative stress.
Specific Aim 2 tests the hypothesis that tissue-specific dysregulation of GHR gene expression with abrogation of hepatic GHR expression and concomitant retention of expression of GHR in the kidney plays a crucial role in the pathogenesis of renal complications of DM. This hypothesis will be tested by analyzing the effect of podocyte- targeted deletion of the GHR gene on DM nephropathy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049845-12
Application #
7502745
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Ketchum, Christian J
Project Start
1996-06-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
12
Fiscal Year
2008
Total Cost
$313,725
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Lu, Chunxia; Kumar, P Anil; Sun, Jinhong et al. (2013) Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. J Biol Chem 288:15725-35
Kumar, P Anil; Brosius 3rd, Frank C; Menon, Ram K (2011) The glomerular podocyte as a target of growth hormone action: implications for the pathogenesis of diabetic nephropathy. Curr Diabetes Rev 7:50-5
Sun, Jinhong; Kumar, P Anil; Thimmarayappa, Jamuna et al. (2011) Esterase 1 is a novel transcriptional repressor of growth hormone receptor gene expression: a unique noncatalytic role for a carboxyesterase protein. Mol Endocrinol 25:1351-63
Lu, Chunxia; Kumar, P Anil; Fan, Yong et al. (2010) A novel effect of growth hormone on macrophage modulates macrophage-dependent adipocyte differentiation. Endocrinology 151:2189-99
Kumar, P Anil; Kotlyarevska, Kateryna; Dejkhmaron, Prapai et al. (2010) Growth hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of gh with implications for the pathogenesis of diabetic nephropathy. J Biol Chem 285:31148-56
Fan, Yong; Menon, Ram K; Cohen, Pinchas et al. (2009) Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem 284:19937-44
Thomas, Inas H; Saini, Natinder K; Adhikari, Amita et al. (2009) Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation. Pediatr Diabetes 10:492-6