Podocyte injury is a major mechanism for kidney glomerular disease. Retinoids have been found to provide protection in several experimental models of kidney diseases. Recently, we and others have found that all- trans-retinoic acid (atRA) can restore the normal phenotype of podocytes in various disease states. Our novel key observation are: 1) The effects of atRA on podocytes are mediated by cAMP/PKA/CREB pathway and phosphodiesterase 4 (PDE4) inhibitors enhanced the protective effects of atRA. 2) AtRA stimulates MAPK phosphatase 1 (MKP1) expression via the cAMP/CREB pathway. By this mechanism, atRA inhibits HIV-induced MAPK1.2 phosphorylation and high glucose and puromycin-induced p38 phosphorylation. Based on these novel observations, we hypothesize that the cAMP/CREB axis is a major pathway mediating the protective effects of atRA on podocytes. This proposal will help us to elucidate the cellular and molecular mechanism of atRA in podocytes. We propose the following specific aims:
Specific aim 1 : Determine atRA- induced signaling pathways in podocytes. In this aim, we will determine a) the role of cAMP/PKA and its interaction with MAPK in mediating the effects of atRA on podocytes, b) how retinoic acid receptors mediate cAMP production in podocytes.
Specific aim 2 : Determine atRA-activated transcriptional networks in injured podocytes. In this aim, we will determine a) the role of atRA-regulated key transcription factors (TFs) in injured podocytes by emphasizing on the role of CREB, b) the role of CREB-and RARE-mediated genes in podocytes in response to atRA using combined computational and experimental approach.
Specific aim 3 : Validate our in vitro findings by in vivo models. In this aim, we will determine the expression of key signaling molecules, key TFs, and CREB-mediated genes in kidneys of animal models and identify a new therapeutic regime by determining whether treatment of atRA prevent the development or improve established kidney diseases and whether combining atRA with a PDE4 inhibitor provides additional benefits in animal models. Glomerular diseases are the major cause of ESRD and treatment options for glomerular diseases are limited. Discovery of new regimes for these diseases has enormous interest for public health. Our study may lead to discover new targets of intervention for glomerular diseases and identify new therapy regimes of retinoids by enhancing its beneficial effects and reducing its side effects in patients with kidney diseases.
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