title: Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II-induced inflammation and cardiac fibrosis.
abstract: OBJECTIVE
  Inflammatory responses play a pivotal role in the pathogenesis of hypertensive cardiac remodeling. Macrophage recruitment and polarization contribute to the development of cardiac fibrosis. Although serum-glucocorticoid regulated kinase 1 (SGK1) is a key mediator of fibrosis, its role in regulating macrophage function leading to cardiac fibrosis has not been investigated. We aimed to determine the mechanism by which SGK1 regulates the cardiac inflammatory process, thus contributing to hypertensive cardiac fibrosis.
  
  
  RESULTS
  After angiotensin II infusion in mice, cardiac hypertrophy and fibrosis developed in wild-type but not SGK1 knockout mice, with equal levels of hypertension in both groups. Compared with wild-type hearts, SGK1 knockout hearts showed less infiltration of leukocytes and macrophages. Importantly, SGK1 deficiency led to decreased proportion of alternatively activated (M2) macrophages and increased levels of profibrotic cytokines. Angiotensin II infusion induced phosphorylation and nuclear localization of signal transducer and activator of transcription 3 (STAT3) whereas SGK1 knockout hearts showed this effect attenuated. In a 3-dimensional peptide gel culture, inhibition of STAT3 suppressed differentiation into M2 macrophages. Coculture of macrophages with cardiac fibroblasts in 3-dimensional peptide gel stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, SGK1 knockout mice with macrophage deficiency showed reduced fibroblast-to-myofibroblast transition.
  
  
  CONCLUSIONS
  SGK1 may play an important role in macrophage recruitment and M2 macrophage activation by activating the STAT3 pathway, which leads to angiotensin II-induced cardiac fibrosis.
authors.affiliation: Beijing Anzhen Hospital Affiliated to the Capital Medical University, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Jiao
authors.initials: J
authors.lastname: Zheng
authors.forename: Yanjv
authors.initials: Y
authors.lastname: Miao
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Shulan
authors.initials: S
authors.lastname: Qiu
authors.forename: Yalei
authors.initials: Y
authors.lastname: Han
authors.forename: Lixin
authors.initials: L
authors.lastname: Jia
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
authors.forename: Jie
authors.initials: J
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016764:Cell Polarity; D002478:Cells, Cultured; D005355:Fibrosis; D017874:Immediate-Early Proteins / Q000502:physiology*; D007249:Inflammation / Q000209:etiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000804:Angiotensin II; D017874:Immediate-Early Proteins; D017493:Leukocyte Common Antigens; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D000099184:Serum-Glucocorticoid Regulated Kinases; C494087:Stat3 protein, mouse; C516770:Ptprc protein, mouse