title: JAK3/STAT6 Stimulates Bone Marrow-Derived Fibroblast Activation in Renal Fibrosis.
abstract: Renal fibrosis is a final common manifestation of CKD resulting in progressive loss of kidney function. Bone marrow-derived fibroblast precursors contribute significantly to the pathogenesis of renal fibrosis. However, the signaling mechanisms underlying the activation of bone marrow-derived fibroblast precursors in the kidney are not fully understood. In this study, we investigated the role of the Janus kinase 3 (JAK3)/signal transducer and activator of transcription (STAT6) signaling pathway in the activation of bone marrow-derived fibroblasts. In cultured mouse monocytes, IL-4 or IL-13 activated STAT6 and induced expression of α-smooth muscle actin and extracellular matrix proteins (fibronectin and collagen I), which was abolished by a JAK3 inhibitor (CP690,550) in a dose-dependent manner or blocked in the absence of STAT6. In vivo, STAT6 was activated in interstitial cells of the obstructed kidney, an effect that was abolished by CP690,550. Mice treated with CP690,550 accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys compared with vehicle-treated mice. Treatment with CP690,550 also significantly reduced myofibroblast transformation, matrix protein expression, fibrosis development, and apoptosis in obstructed kidneys. Furthermore, STAT6-deficient mice accumulated fewer bone marrow-derived fibroblasts in the obstructed kidneys, produced less extracellular matrix protein, and developed much less fibrosis. Finally, wild-type mice engrafted with STAT6(-/-) bone marrow cells displayed fewer bone marrow-derived fibroblasts in the obstructed kidneys and showed less severe renal fibrosis compared with wild-type mice engrafted with STAT6(+/+) bone marrow cells. Our results demonstrate that JAK3/STAT6 has an important role in bone marrow-derived fibroblast activation, extracellular matrix production, and interstitial fibrosis development.
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Jingyin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas;
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas yanlinw@bcm.edu.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes; D058628:Myofibroblasts / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050800:STAT6 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D018793:Interleukin-13; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; C479163:tofacitinib; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3
keywords: cell signaling; cytokines; extracellular matrix; fibroblast; renal fibrosis