HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy

Man Chen, Madhav C. Menon, Wenlin Wang, Jia Fu, Zhengzi Yi, Zeguo Sun, Jessica Liu, Zhengzhe Li, Lingyun Mou, Khadija Banu, Sui-Wan Lee, Ying Dai, Nanditha Anandakrishnan, Evren U. Azeloglu, Kyung Lee, Weijia Zhang, Bhaskar Das (), John Cijiang He () and Chengguo Wei ()
Additional contact information
Man Chen: Icahn School of Medicine at Mount Sinai
Madhav C. Menon: Yale School of Medicine
Wenlin Wang: Icahn School of Medicine at Mount Sinai
Jia Fu: Icahn School of Medicine at Mount Sinai
Zhengzi Yi: Icahn School of Medicine at Mount Sinai
Zeguo Sun: Icahn School of Medicine at Mount Sinai
Jessica Liu: Icahn School of Medicine at Mount Sinai
Zhengzhe Li: Icahn School of Medicine at Mount Sinai
Lingyun Mou: Icahn School of Medicine at Mount Sinai
Khadija Banu: Yale School of Medicine
Sui-Wan Lee: Icahn School of Medicine at Mount Sinai
Ying Dai: Icahn School of Medicine at Mount Sinai
Nanditha Anandakrishnan: Icahn School of Medicine at Mount Sinai
Evren U. Azeloglu: Icahn School of Medicine at Mount Sinai
Kyung Lee: Icahn School of Medicine at Mount Sinai
Weijia Zhang: Icahn School of Medicine at Mount Sinai
Bhaskar Das: Long Island University
John Cijiang He: Icahn School of Medicine at Mount Sinai
Chengguo Wei: Icahn School of Medicine at Mount Sinai

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Renal inflammation and fibrosis are the common pathways leading to progressive chronic kidney disease (CKD). We previously identified hematopoietic cell kinase (HCK) as upregulated in human chronic allograft injury promoting kidney fibrosis; however, the cellular source and molecular mechanisms are unclear. Here, using immunostaining and single cell sequencing data, we show that HCK expression is highly enriched in pro-inflammatory macrophages in diseased kidneys. HCK-knockout (KO) or HCK-inhibitor decreases macrophage M1-like pro-inflammatory polarization, proliferation, and migration in RAW264.7 cells and bone marrow-derived macrophages (BMDM). We identify an interaction between HCK and ATG2A and CBL, two autophagy-related proteins, inhibiting autophagy flux in macrophages. In vivo, both global or myeloid cell specific HCK-KO attenuates renal inflammation and fibrosis with reduces macrophage numbers, pro-inflammatory polarization and migration into unilateral ureteral obstruction (UUO) kidneys and unilateral ischemia reperfusion injury (IRI) models. Finally, we developed a selective boron containing HCK inhibitor which can reduce macrophage pro-inflammatory activity, proliferation, and migration in vitro, and attenuate kidney fibrosis in the UUO mice. The current study elucidates mechanisms downstream of HCK regulating macrophage activation and polarization via autophagy in CKD and identifies that selective HCK inhibitors could be potentially developed as a new therapy for renal fibrosis.

Date: 2023
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DOI: 10.1038/s41467-023-40086-3

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