Cellular and Molecular Mechanisms of Renal Fibrosis

描述（由申请人提供）：慢性肾脏疾病（CKD）是一个日益严重的公共卫生问题，影响超过2600万美国人。CKD的一个关键病理特征是肾纤维化伴细胞外基质积累增加。肾间质纤维化的特点是成纤维细胞活化，细胞外基质过度产生和沉积，导致肾实质破坏，肾功能进行性丧失。目前对这种毁灭性疾病的治疗选择有限，而且往往无效。因此，更好地了解肾纤维化的细胞和分子机制对于制定治疗这种进行性肾脏疾病的有效策略至关重要。我们研究了引发和控制肾纤维化的因素

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a growing public health problem that affects more than 26 million Americans. A key pathologic feature of CKD is renal fibrosis with increased accumulation of extracellular matrix. Renal interstitial fibrosis is characterized by fibroblast activation and excessive production and deposition of extracellular matrix, which leads to the destruction of renal parenchyma and progressive loss of kidney function. The current therapeutic options for this devastating condition are limited and often ineffective. Therefore, a better understanding of the cellular and molecular mechanisms underlying renal fibrosis is essential for developing effective strategies for the treatment of thi progressive kidney disorder. We have studied the factors initiating and controlling renal fibrosis in a model of ureteral obstruction and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation of renal fibrosis. Our studies demonstrate that the fibrosis associated with obstructive nephropathy arises from the formation of bone marrow-derived fibroblasts which accumulate in the kidney. The presence and development of these fibroblasts from a CD45+ mononuclear precursor population appear to be driven by and dependent upon induction of the chemokine, CXCL16, in renal tubular epithelial cells and is prevented by genetic deletion of CXCL16. The induction of myeloid fibroblasts is associated with striking induction of IL13, the Th2 lymphokine, which we have shown to be obligate for the induction of myeloid fibroblasts in vitro. In this application, we plan to examine and characterize the immune-inflammatory mechanism arising from renal injury to further understand the cellular and molecular mechanisms of renal fibrosis. Our central hypothesis is that pathologic renal interstitial fibrosis arises from immune-inflammatory dysregulation associated with induction of the chemokine - CXCL16 and the cytokine - adiponectin. We propose that CXCL16 initiates the uptake of a unique myeloid mononuclear cell population obligate to the resultant fibrotic phenotype and adiponectin activates these cells to M2 macrophages and myeloid fibroblasts. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of CXCL16/CXCR6 in the uptake of bone marrow-derived monocytes into the kidney. Specific Aim 2 is to examine the role of adiponectin signaling in the activation of bone marrow-derived monocytes to M2 macrophages and myeloid fibroblasts. In summary, we plan to utilize biological and genetic approaches to study the role of bone marrow- derived mononuclear cells in the pathogenesis of renal fibrosis. Our plans are directed at understanding the complex biology of these cells and how they are recruited into the kidney, polarized to M2 macrophages, and develop into mature fibroblasts. Results from our studies will provide a new understanding of the molecular and cellular bases of renal fibrosis and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease.