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Novel Regulators of Growth Hormone Receptor gene expression and Growth Hormone Action

Pituitary growth hormone (GH) is essential for post-natal growth, differentiation and metabolism. These somatogenic and metabolic actions of GH are mediated at cellular level via interaction with the GH receptor (GHR). Regulation of GHR gene expression is a nodal point in the biological role(s) of the GH/GHR axis. Deregulation of the GH/GHR axis such as 1) decreased GHR expression and 2) elevated GH levels are implicated in the abnormalities of poorly control type1 diabetes. In a prior study, we reported that free fatty acids (FFA) directly inhibit GHR expression, and characterized FFA-response elements (FARE) in the GHR gene promoter. In the course of the investigation, we obtained evidence to suggest that Esterase1 (ES1) interacts with the FARE to mediate the effects of FFA on GHR gene expression. In my presentation, I will detail studies that establish a novel non-catalytic role for ES1, as a repressor of GHR gene transcription. GH excess results in structural and functional changes in the kidney and is implicated as a causative factor in the development of diabetic nephropathy (DN). Glomerular podocytes are the major barrier to the filtration of serum proteins, and altered podocyte function is a key event in the pathogenesis of DN. We have previously shown that podocytes are a target for GH action. To elucidate the molecular basis for the effects of GH on the podocyte, we conducted microarray and RT-quantitative PCR analyses of immortalized human podocytes and identified zinc finger E-box-binding homeobox 2 (ZEB2) to be up-regulated in a GH dependent manner. We established that the GH-dependent increase in ZEB2 expression results increased podocyte permeability to albumin. I will be presenting our data that demonstrate GH’s role in the pathogenesis of microalbuminuria of DN.