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.

Public Health Relevance

Our proposed research is highly relevant to public health because understanding the biology of bone marrow-derived cells and their roles in the development of renal fibrosis will provide a new research direction in chronic kidney disease and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease. Therefore, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human illness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095835-02
Application #
8539601
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2012-09-03
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$328,474
Indirect Cost
$118,586
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Xia, Yunfeng; Yan, Jingyin; Jin, Xiaogao et al. (2014) The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis. Kidney Int 86:327-37
Chen, Jiyuan; Xia, Yunfeng; Lin, Xia et al. (2014) Smad3 signaling activates bone marrow-derived fibroblasts in renal fibrosis. Lab Invest 94:545-56
Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin et al. (2014) CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis. Arterioscler Thromb Vasc Biol 34:1422-8
Xia, Yunfeng; Entman, Mark L; Wang, Yanlin (2013) Critical role of CXCL16 in hypertensive kidney injury and fibrosis. Hypertension 62:1129-37
Yang, Jun; Lin, Song-Chang; Chen, Gang et al. (2013) Adiponectin promotes monocyte-to-fibroblast transition in renal fibrosis. J Am Soc Nephrol 24:1644-59
Xia, Yunfeng; Entman, Mark L; Wang, Yanlin (2013) CCR2 regulates the uptake of bone marrow-derived fibroblasts in renal fibrosis. PLoS One 8:e77493
Jin, Xiaogao; Chen, Jiyuan; Hu, Zhaoyong et al. (2013) Genetic deficiency of adiponectin protects against acute kidney injury. Kidney Int 83:604-14