Cellular Signaling in Renal Pathophysiology

描述（由申请人提供）：进行性肾病的特征为肾小球和间质细胞增殖、循环炎性细胞的流入和活化以及细胞外基质大分子的过度产生和沉积。该基金支持的先前研究已经证明了cAMP-PKA途径在调节系膜细胞（MC）增殖中的重要性，并确定了环3 '-5'核苷酸磷酸二酯酶（PDE）同工酶作为治疗急性肾损伤的治疗剂的潜在作用。然而，目前尚不清楚PDE抑制剂是否会阻止慢性肾脏疾病的发展或减缓其进展。待检验的中心假设是，cAMP同工酶特异性PDE抑制剂通过与关键的促有丝分裂、炎症和基质信号传导途径的负串扰，能够预防进行性肾病的发生和发展。最近的研究提供了证据表明，这些关键途径是通过cAMP-PKA和TGF-β 1信号之间的相互作用进行调节的。初步研究将确定cAMP诱导TGF-β表达的机制，并将描述cAMP和TGF-β 1相互作用抑制MC有丝分裂的途径（特异性目的1）。在特定目的2中，将检验PDE 4抑制剂通过抑制TGF-β刺激的MAPK途径抑制MCP-1表达从而导致NF-κ B下调的假设。在具体目标3中，将定义cAMP-PKA途径在IV型胶原蛋白产生和catalysts中的作用。将检验cAMP激动剂能够通过下调ERK和/或p38通路“解偶联”瘢痕对升高的TGF-β 1水平的反应的假设。将在慢性Thy 1模型中确定这些研究的体内相关性，以确定cAMP-PKA通路在MC增殖、炎症介质产生和基质产生中的作用（特定目的4）。通过仔细的半定量组织病理学分析和急性和慢性肾损伤标志物的鉴定，将有可能鉴定与急性损伤转化为慢性进行性肾病相关的适应不良信号通路，并确定PDE抑制剂在预防或改善该过程中的作用。这些研究将揭示进展性肾脏疾病的基本机制，并可能为设计更新，更具体的药物治疗慢性肾脏疾病提供合理的基础。

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.