Chronic kidney disease is a growing public health problem that affects more than 26 million Americans. A key pathologic feature of chronic kidney disease is renal fibrosis. Renal 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 to end-stage renal disease. 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 fibrotic kidney disorder. We have studied the factors initiating and controlling renal fibrosis and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation and development of renal fibrosis. Our studies have demonstrated that the fibrosis arises from kidney injury is associated with the formation of bone marrow-derived fibroblasts that accumulate in the kidney. The presence and accumulation of these fibroblasts from a CD45+ mononuclear precursor population and the development of renal fibrosis are driven by and dependent upon induction of the chemokine CXCL16 in renal tubular epithelial cells and is prevented by genetic deletion of CXCL16, or its receptor, CXCR6. Furthermore, the accumulation of myeloid fibroblasts is associated with striking induction of Th2 cytokines, which activate signal transducer and activator of transcription 6 (STAT6) to stimulate myeloid fibroblast activation and fibrogenesis in the kidney. Activated STAT6 induces expression of histone H3K27 demethylase, Jumonji domain-containing protein 3 (JMJD3), resulting in histone H3K27 demethylation and myeloid fibroblast activation. In this renewal application, we plan to examine and characterize the role of STAT6-JMJD3 signaling in myeloid fibroblast activation to further understand the cellular and molecular mechanisms of renal fibrosis. Our central hypothesis is that Th2 cytokines activate STAT6 signaling resulting in JMJD3 induction, histone H3K27 demethylation, myeloid fibroblast activation, and fibrogenesis. To test our hypothesis, we will pursue the following Specific Aims:
Specific Aim 1 is to determine the role of STAT6 signaling in the activation of bone marrow-derived fibroblasts.
Specific Aim 2 is to examine whether JMJD3 mediates bone marrow-derived fibroblast activation. In summary, we plan to utilize molecular, cellular, pharmacological, and genetic approaches to study the role of STAT6-JMJD3 signaling in myeloid fibroblast activation and development of renal fibrosis. Results from our studies will provide a new understanding of the cellular and molecular mechanisms of renal fibrosis and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease.
Chronic kidney disease affects more than 26 million Americans. Understanding the molecular mechanisms underlying activation of bone marrow-derived fibroblasts and development of renal fibrosis could lead to novel therapeutic strategies for the treatment of chronic kidney disease. Therefore, the proposed research is highly relevant to NIH?s mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disease.
|Wang, Yuguo; Jia, Li; Hu, Zhaoyong et al. (2018) AMP-activated protein kinase/myocardin-related transcription factor-A signaling regulates fibroblast activation and renal fibrosis. Kidney Int 93:81-94|
|Peng, Hui; Wang, Qianqian; Lou, Tanqi et al. (2017) Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat Commun 8:1493|
|Liang, Hua; Zhang, Zhengmao; Yan, Jingyin et al. (2017) The IL-4 receptor ? has a critical role in bone marrow-derived fibroblast activation and renal fibrosis. Kidney Int 92:1433-1443|
|Zhou, Jun; Jia, Li; Hu, Zhaoyong et al. (2017) Pharmacological Inhibition of PTEN Aggravates Acute Kidney Injury. Sci Rep 7:9503|
|Yu, Rizhen; Chen, Ji-An; Xu, Jing et al. (2017) Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney disease. J Cachexia Sarcopenia Muscle 8:327-341|
|Liu, Xinyan; Yu, Rizhen; Sun, Lijing et al. (2017) The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease. Kidney Int 92:336-348|
|Li, Jia; An, Changlong; Kang, Lei et al. (2017) Recent Advances in Magnetic Resonance Imaging Assessment of Renal Fibrosis. Adv Chronic Kidney Dis 24:150-153|
|Peng, Hui; Li, Yuanqing; Wang, Cheng et al. (2016) ROCK1 Induces Endothelial-to-Mesenchymal Transition in Glomeruli to Aggravate Albuminuria in Diabetic Nephropathy. Sci Rep 6:20304|
|Peng, Hui; Cao, Jin; Yu, Rizhen et al. (2016) CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation. J Am Soc Nephrol 27:509-19|
|Liang, Hua; Zhang, Zhengmao; He, Liqun et al. (2016) CXCL16 regulates cisplatin-induced acute kidney injury. Oncotarget 7:31652-62|
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