Macrophage Dectin-1 mediates Ang II renal injury through neutrophil migration and TGF-β1 secretion

  • Cell Mol Life Sci. 2023 Jun 20;80(7):184. doi: 10.1007/s00018-023-04826-4.
Shiju Ye  #  1  2  3 ,  He Huang  #  1 ,  Yun Xiao  #  1 ,  Xue Han  2 ,  Fengjie Shi  1 ,  Wu Luo  2  4 ,  Jiawen Chen  1 ,  Yang Ye  1 ,  Xia Zhao  2 ,  Weijian Huang  3 ,  Yi Wang  4 ,  Dongwu Lai  1 ,  Guang Liang  5  6 ,  Guosheng Fu  7
Affiliations
  • 1. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310020, Zhejiang, China.
  • 2. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China.
  • 3. Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 4. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 5. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China. [email protected].
  • 6. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
  • 7. Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310020, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 37340199 DOI: 10.1007/s00018-023-04826-4
Abstract

Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk Inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through SMAD3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction.

Keywords
Angiotensin II; Chronic kidney disease; Dectin-1; Hypertension; TGF-β1.
Products