Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy

Yiwen Cao; Jingli Xiong; Xueping Guan; Simin Yin; Junqi Chen; Shengliang Yuan; Hong Liu; Shuyin Lin; Yuan Zhou; Jianguang Qiu; Dejuan Wang; Bihao Liu; Jiuyao Zhou

doi:10.1016/j.phymed.2023.154901

Paeoniflorin suppresses kidney inflammation by regulating macrophage polarization via KLF4-mediated mitophagy

Phytomedicine. 2023 Jul 25:116:154901. doi: 10.1016/j.phymed.2023.154901. Epub 2023 May 24.

Authors

Yiwen Cao¹, Jingli Xiong¹, Xueping Guan¹, Simin Yin¹, Junqi Chen¹, Shengliang Yuan¹, Hong Liu¹, Shuyin Lin¹, Yuan Zhou¹, Jianguang Qiu², Dejuan Wang², Bihao Liu³, Jiuyao Zhou⁴

Affiliations

¹ Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China.
² Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China.
³ Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, Guangdong, China. Electronic address: liubh26@mail.sysu.edu.cn.
⁴ Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong, China. Electronic address: zhoujiuyao@tom.com.

PMID: 37247587
DOI: 10.1016/j.phymed.2023.154901

Abstract

Background: Macrophages M1 polarization involved in the process of renal inflammatory injury, is a well-established hallmark of chronic kidney disease (CKD). Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from Paeonia lactiflora, revealed renal anti-inflammatory activities in our previous study. However, the potential molecular mechanism of PF on CKD remains unknown.

Purpose: The present study aims to investigate the regulation of PF on macrophage polarization in CKD.

Methods: A CKD model was established by cationic bovine serum albumin and a murine macrophage cell line RAW264.7 induced with lipopolysaccharide (LPS) were used to clarify the underlying mechanisms of PF in CKD.

Results: Results showed that PF exhibited favorable protective effects on CKD model mice by promoting renal function, ameliorating renal pathological injury and podocyte damage. Furthermore, PF inhibited the infiltration of M1 macrophage marker CD68 and iNOS in kidney tissue, but increased the proportion of M2 macrophage marker CD206. In RAW264.7 cells stimulated with LPS, the levels of cytokines including IL-6, IL-1β, TNF-α, MCP-1 were lessened under PF treatment, while the levels of Arg1, Fizz1, IL-10 and Ym-1 were augmented. These results indicated that PF promoted macrophage polarization from M1 to M2 in vivo and in vitro. More importantly, PF repaired the damaged mitochondria through increasing mitochondrial membrane potential and reducing ROS accumulation. The mitophagy-related proteins PINK1, Parkin, Bnip3, P62 and LC3 were up-regulated by PF, accompanied by the incremental expressions of Krüppel-like transcription factor 4 (KLF4). Moreover, the promotion of mitophagy and inhibition of M1 macrophage polarization owing to PF were reversed by mitophagy inhibitor Mdivi-1 or silencing KLF4.

Conclusion: Overall, PF suppressed renal inflammation by promoting macrophage polarization from M1 to M2 and inducing mitophagy via regulating KLF4. It is expected to provide a new strategy for exploring the effects of PF in treating CKD.

Keywords: Chronic kidney disease; Krüppel-like transcription factor 4; Macrophage polarization; Mitophagy; Paeoniflorin.

MeSH terms

Animals
Inflammation / metabolism
Kidney / pathology
Lipopolysaccharides / pharmacology
Macrophages
Mice
Mitophagy
Monoterpenes / pharmacology
Nephritis* / pathology
Renal Insufficiency, Chronic*

Substances

peoniflorin
Lipopolysaccharides
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
Monoterpenes