Recent studies documented a key importance of cyclic-3', 5' -nucleotide phosphodiesterase (PDE) isozymes in cAMP signaling pathways that regulate biology and pathobiology of renal cells. The proposed investigations are based on a working hypothesis that pathobiologic responses of mesangial cells (MC) to immune-inflammatory stimuli can be modulated and selectively suppressed in vitro and in vivo by pharmacotherapeutic interventions that are targeted to intracellular signaling pathways and their mutual interactions. The main target points for modulation of the cAMP and cGMP signaling pathways are PDE isozymes. The cAMP signaling can via """"""""negative crosstalk"""""""" with other signaling pathways suppress excessive proliferation of MC and also generation of reactive oxygen metabolites (ROM) in MC. In vitro studies will elucidate the pattern of isoforms, localization, and regulation of PDE isozymes in rat MC in primary cell culture, and then determine their sensitivity to select antagonists. Isozymes of protein kinase A (PKA), an essential link in c AMP pathway, will be examined in MC, especially in relationship to PDE-directed pools of cAMP and functional end-responses of MC. The role of cGMP signaling in MC will be explored as well. The major goal is the delineation of the """"""""negative crosstalk"""""""" by which cAMP-PKA inhibits the mitogen-activated signaling pathways that control MC proliferation; we will also elucidate the antimitogenic effect of cGMP signaling. Further studies will determine the biochemical basis of the """"""""negative crosstalk"""""""" by which cAMP-PKA pathway inhibits ROM generation by NADPH oxidase in MC. Finally, in vivo, the pathogenic mechanisms and novel pharmacotherapies will be studied in the rat model of mesangial proliferative glomerulonephritis (MSGN), """"""""anti-Thy-1.1-GN,"""""""" in which pathobiology of MC plays a dominant role. Pharmacotherapeutic interventions, mainly targeted to PDE isozymes and PKA isozymes, will be examined for their efficacy to prevent, block, or reverse MSGN of various grades of severity, and at different stages of MSGN development. These studies will establish a paradigm for novel """"""""signal transduction-targeted"""""""" pharmacotherapies of MSGN with use of PDE isozyme antagonists and, prospectively, for treatment of other types of glomerulonephritis.
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