Growth hormone (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 and/or reduced podocyte number 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 dose-and time-dependent manner. We established that the GH-dependent increase in ZEB2 levels is associated with increased transcription of a ZEB2 natural antisense transcript required for efficient translation of the ZEB2 transcript. GH down-regulated expression of E-and P-cadherins, targets of ZEB2, and inhibited E-cadherin promoter activity. Mutation of ZEB2 binding sites on the E-cadherin promoter abolished this effect of GH on the E-cadherin promoter. Whereas GH increased podocyte permeability to albumin in a paracellular albumin influx assay, shRNA-mediated knockdown of ZEB2 expression abrogated this effect. We conclude that GH increases expression of ZEB2 in part by increasing expression of a ZEB2 natural antisense transcript. GH-dependent increase in ZEB2 expression results in loss of P-and E-cadherins in podocytes and increased podocyte permeability to albumin. Decreased expression of P-and E-cadherins is implicated in podocyte dysfunction and epithelial-mesenchymal transition observed in DN. We speculate that the actions of GH on ZEB2 and P-and E-cadherin expression play a role in the pathogenesis of microalbuminuria of DN. Pituitary growth hormone (GH)5 is essential for postnatal growth in mammals. In addition to growth, GH affects the metabolism of fat, protein, and carbohydrate (1). GH exerts these actions both by its direct effect on target organs and by stimulating the production of insulin-like growth factor-1 (IGF-1). At the tissue level, these pleiotropic actions of GH result from the interaction of GH with a specific cell surface receptor, the GH receptor (GHR). Whereas the GHR is ubiquitously expressed, the role and effects of GH have been most intensely investigated in organs and tissues such as liver, bone, muscle, and adipocytes in which GHR expression is substantial and are thus considered canonical targets of GH action. However, recent reports have highlighted the biological effects and physiological relevance of GH action in non-canonical targets such as the blastocyst (2), colonic epithelial cells (3), cardiomyocytes (4), and neurons (5).GH excess in both the human (acromegaly) and in transgenic animal models is characterized by significant structural and functional changes in the kidney (6 -8). An overactive GH/ GHR axis is implicated as a causative factor in the development of diabetic nephropathy (9 -11). Our previous study...