DESCRIPTION (provided by applicant): Progressive renal disease is characterized by the proliferation of glomerular and interstitial cells, the influx and activation of circulating inflammatory cells, and the excessive production and deposition of extracellular matrix macromolecules. Previous studies supported by this grant have demonstrated the importance of the cAMP-PKA pathway in regulation of mesangial cell (MC) proliferation and have identified a potential role of cyclic 3'-5' nucleotide phosphodiesterase (PDE) isozymes as therapeutic agents to treat acute renal injury. However, it is not known whether PDE inhibitors will prevent the development or slow the progression of chronic renal disease. The central hypothesis to be tested is that cAMP isozyme-speciflc PDE inhibitors, through negative crosstalk with critical mitogenic, inflammatory, and matrix signaling pathways, are capable of preventing the onset and development of progressive renal disease. Recent studies have provided evidence that these critical pathways are regulated through interactions between cAMP-PKA and TGF-beta1 signaling. Initial studies will define the mechanism by which cAMP induces TGF-beta expression and will delineate pathways through which cAMP and TGF-beta1 interact to suppress MC mitogenesis (Specific Aim 1). In Specific Aim 2, the hypothesis that PDE4 inhibitors suppress MCP-1 expression through inhibition of TGF-beta-stimulated MAPK pathway(s) leading to down regulation of Nf-KB will be tested. In Specific Aim 3, the role of the cAMP-PKA pathway in collagen IV production and catabolism will be defined. The hypothesis that cAMP agonists are capable of "uncoupling" the cicatricial response to elevated TGF-beta1 levels through down regulation of the ERK and/or p38 pathways will be tested. The in vivo relevance of these studies to define the role of the cAMP-PKA pathway in MC proliferation, production of inflammatory mediators, and matrix production will be established in the chronic Thy 1 model (Specific Aim 4). Through careful semi-quantitative histopathologic analysis and identification of markers of acute and chronic renal injury, it will be possible to identify maladaptive signaling pathways that are associated with the transformation of acute injury into chronic, progressive renal disease and to define the role of PDE inhibitors in preventing or ameliorating this process. These studies will reveal insights into basic mechanisms underlying progressive renal disease and may provide the rational basis for the design of newer, more specific pharmacotherapeutic agents to treat chronic renal disease.
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