STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation.

Autor: Lee SH; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea.; Department of Pharmacology, Seoul National University, Seoul, Republic of Korea., Kim KH; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea., Lee SM; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea., Park SJ; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea., Lee S; Department of Internal Medicine, Division of Nephrology, Kangwon National University Hospital, Chuncheon, Gangwon-Do, Republic of Korea., Cha RH; Biomedical Research Institute, Seoul National University Hospital, Hospital, Seoul, Republic of Korea., Lee JW; Nephrology Clinic, National Cancer Center of Korea, Seoul, Republic of Korea., Kim DK; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.; Department of Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea., Kim YS; Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.; Department of Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea., Ye SK; Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea. sangkyu@snu.ac.kr.; Department of Pharmacology, Seoul National University, Seoul, Republic of Korea. sangkyu@snu.ac.kr., Yang SH; Department of Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea. ysh5794@snu.ac.kr.; Biomedical Research Institute, Seoul National University Hospital, Hospital, Seoul, Republic of Korea. ysh5794@snu.ac.kr.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Oct 04; Vol. 22 (1), pp. 476. Date of Electronic Publication: 2024 Oct 04.
DOI: 10.1186/s12964-024-01841-1
Abstrakt: Background: Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3's role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear.
Methods: Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6-24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model.
Results: In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0-6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11b high F4/80 low and CD11b low F4/80 high ), exhibited population changes, with an increase in the CD11b high F4/80 low population and a decrease in the CD11b low F4/80 high macrophages. Corresponding to the FACS results, the tubular injury score, NGAL, F4/80, and p-STAT3 expression in the tubular regions were elevated. STAT3 inhibitor injection in L-AKI and L-CKD mice reduced renal injury and fibrosis. M2-type subpopulation with CD206 in CD11b low F4/80 high population increased in the Stattic-treated group compared with that in the LPS-alone group in the L-AKI model. Additionally, STAT3 inhibitor reduced inflammation driven by LPS-stimulated macrophages and epithelial cells injury in the co-culture system. Transcriptomic profiling identified 3 common genes in the JAK-STAT, TLR, and TNF signaling pathways and 11 common genes in the LPS with macrophage response. The PI3K-AKT (IL-6, Akt3, and Pik3r1) and JAK-STAT pathways were determined as potential Stattic targets. Further confirmation through mRNA and protein expressions analyses showed that Stattic treatment reduced inflammation in the L-AKI and fibrosis in the L-CKD mice.
Conclusions: STAT3 blockade effectively mitigated inflammation by retrieving the CD11b low F4/80 high population, further emphasizing the role of STAT3-associated macrophage-driven inflammation in kidney injury.
(© 2024. The Author(s).)
Databáze: MEDLINE
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