Regulation of podocyte function by angiotensin II (ANGII): Glomerular epithelial cells (podocytes) are a critical component of the glomerular filtration barrier. Podocyte damage is associated with proteinuria and progressive loss of kidney function. A large body of evidence indicates that glomerular damage is mediated, at least in part, by ANGII through type 1 (AT1) and type 2 (AT2) receptor subtypes. Within the glomerulus, ANGII receptors are expressed on podocytes,endothelial cells and mesangial cells. Podocytes express both AT1 and AT2 receptors. Activation of this receptor system presumably regulates podocyte function and, in disease states, may promote podocyte injury. In many cell types as well as animal models, the injury promoting effects of ANGII are mediated by AT1 receptors and may be negatively modulated by AT2 receptors. In this regard, our preliminary data suggest that ATl-induced activation of the Gq alpha-subunit (Galphaq) plays a key role in mediating the damaging effects of ANGII both in vitro and in vivo. Based on this preliminary work, we hypothesized that: AT1 receptors have injury promoting effects in glomerular podocytes that are largely mediated through Galphaq-dependent pathways and are modulated by the opposing actions of AT2 receptors. In the proposed studies, we will investigate this hypothesis focusing on three specific aims. First, we will identify AT1- and AT2-dependent signaling pathways that regulate proliferation, protein synthesis, and apoptosis in cultured podocytes using pharmacological and molecular biological techniques. Based on our preliminary results, in second specific aim #2, we will define the role of Galphaq-coupled pathways in promoting podocyte injury in vivo by expressing a constitutively active form of Galphaq (GalphaqQ>L)in podocytes using the mouse nephrin promoter. Lastly, we will determine the role AT1 receptors in promoting glomerular injury specifically in podocytes as well as the role of podocyte AT2 receptors in modulating both AT1- and Galphaq-dependentrenal damage. In these studies, we will use transgenic techniques to overexpress either AT1 or AT2 receptors specifically on glomerular podocytes. After determining the effect of the transgenes in unmanipulated mice, we will use our transgenic animals to investigate the severity of renal damage induced by: 1. infusion of ANGII, 2. co-expression of AT2 receptors and GalphaqQ>L in podocytes, and 3. podocyte injury using a model developed in our laboratory. These studies should provide new, important insights into the role of podocyte ANGII receptors in promoting glomerular injury in disease states. Understanding the biochemical mechanisms that regulate glomerular disease processes may provide a rationale strategy for making therapeutic decisions and could lead to the development of novel strategies for treating glomerular diseases.
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