MON-476 Growth Hormone and the Glomerular Podocyte: Studies of Podocyte-Specific Growth Hormone Receptor Gene Deletion in Mice

Abstract

Previous research has suggested a role for growth hormone (GH) in the development of kidney disease. Evidence of increased glomerular size and sclerosis in bovine GH (bGH) overproducing animals suggests that excess GH action may cause or exacerbate glomerular damage. Within the glomerulus, the podocyte plays the role of forming a filtration barrier called the slit diaphragm. This cell is known to be dysfunctional in many models of nephropathy and is also a direct target of GH. To explore the mechanisms by which GH impacts the glomerulus, we have developed a transgenic mouse, the podocyte-specific GH receptor gene-disrupted mouse (podGHR-/-). These mice were generated on a C57BL/6J background using Cre-Lox transgenic methods. To examine the effects of high GH levels on the podocyte, these mice were crossed with bovine GH (bGH) overproducing mice and studied at several time points over the course of a year, alongside wild-type control mice and podGHR-/- mice lacking bGH overexpression. Various metabolic and physiologic assays were performed on these mice, including glomerular filtration rate (GFR) testing, glucose and insulin tolerance testing, body composition analysis, and urine & serum analysis. Histological analyses were also performed. Podocyte-specific GHR gene-deletion was associated with increased GFR in male podGHR-/- mice at 54 weeks of age, and with decreased GFR in male podGHR-/- mice with bGH overexpression at 54 weeks of age. PodGHR-/- male mice exhibited significantly decreased total kidney hydroxyproline content at 54 weeks of age as well as decreased glomerular trichrome stain deposition. Both male and female podGHR-/- mice showed decreased glomerular periodic acid Schiff stain deposition at 54 weeks of age. These results suggest a role for podocyte GH activity in the regulation of GFR in the aging and diseased kidney, as well as a role for GH in directing the deposition of collagen and glycosaminoglycans in glomerulus via the podocyte.