Affiliation:
1. Division of Nephrology, Department of Medicine University of Connecticut School of Medicine Farmington Connecticut USA
2. Department of Immunology University of Connecticut School of Medicine Farmington Connecticut USA
3. Department of Cell Biology University of Connecticut School of Medicine Farmington Connecticut USA
4. Institute for Systems Genomics University of Connecticut Farmington Connecticut USA
5. Renal Section, Veterans Affairs Connecticut Healthcare System West Haven Connecticut USA
Abstract
Background and PurposeRenal fibrosis is a common feature of chronic kidney disease. Myeloid fibroblasts and macrophages contribute significantly to the pathogenesis of renal fibrosis. However, the molecular mechanisms underlying myeloid fibroblast activation and macrophage polarization are not fully understood. In this study, we examined the role of Jumonji domain‐containing protein‐3 (JMJD3) in myeloid fibroblast activation, macrophage polarization, and renal fibrosis development in a preclinical model of obstructive nephropathy.Experimental ApproachTo examine the role of JMJD3 in renal fibrosis, we generated mice with global or myeloid cell‐specific deletion of JMJD3, and we treated wild‐type mice with vehicle or GSK‐J4 (selective JMJD3 inhibitor). Mice were subjected to unilateral ureteral obstructive injury to induce renal fibrosis.Key ResultsJMJD3 expression was significantly increased in the kidneys during the development of renal fibrosis, which was associated with an increase in H3K27 dimethylation. Mice with either global or myeloid JMJD3 deficiency exhibited significantly reduced total collagen deposition and extracellular matrix protein production, myeloid fibroblast activation and M2 macrophage polarization in the obstructed kidney. Moreover, IFN regulatory factor 4, a mediator of M2 macrophage polarization, was significantly induced in the obstructed kidneys, which was abolished by JMJD3 deficiency. Furthermore, pharmacological inhibition of JMJD3 with GSK‐J4 attenuated kidney fibrosis, reduced myeloid fibroblast activation and suppressed M2 macrophage polarization in the obstructed kidney.Conclusion and ImplicationsOur study identifies JMJD3 as a critical regulator of myeloid fibroblast activation, macrophage polarization, and renal fibrosis development. Therefore, JMJD3 may represent a promising therapeutic target for chronic kidney disease.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
U.S. Department of Veterans Affairs
Cited by
16 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献