PMID- 38314821 OWN - NLM STAT- MEDLINE DCOM- 20240304 LR - 20240304 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 13 DP - 2024 Feb 5 TI - PSTPIP2 ameliorates aristolochic acid nephropathy by suppressing interleukin-19-mediated neutrophil extracellular trap formation. LID - 10.7554/eLife.89740 [doi] LID - e89740 AB - Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by herbal medicines. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2) and neutrophil extracellular traps (NETs) play important roles in kidney injury and immune defense, respectively, but the mechanism underlying AAN regulation by PSTPIP2 and NETs remains unclear. We found that renal tubular epithelial cell (RTEC) apoptosis, neutrophil infiltration, inflammatory factor, and NET production were increased in a mouse model of AAN, while PSTPIP2 expression was low. Conditional knock-in of Pstpip2 in mouse kidneys inhibited cell apoptosis, reduced neutrophil infiltration, suppressed the production of inflammatory factors and NETs, and ameliorated renal dysfunction. Conversely, downregulation of Pstpip2 expression promoted kidney injury. In vivo, the use of Ly6G-neutralizing antibody to remove neutrophils and peptidyl arginine deiminase 4 (PAD4) inhibitors to prevent NET formation reduced apoptosis, alleviating kidney injury. In vitro, damaged RTECs released interleukin-19 (IL-19) via the PSTPIP2/nuclear factor (NF)-kappaB pathway and induced NET formation via the IL-20Rbeta receptor. Concurrently, NETs promoted apoptosis of damaged RTECs. PSTPIP2 affected NET formation by regulating IL-19 expression via inhibition of NF-kappaB pathway activation in RTECs, inhibiting RTEC apoptosis, and reducing kidney damage. Our findings indicated that neutrophils and NETs play a key role in AAN and therapeutic targeting of PSTPIP2/NF-kappaB/IL-19/IL-20Rbeta might extend novel strategies to minimize Aristolochic acid I-mediated acute kidney injury and apoptosis. CI - (c) 2024, Du, Xu et al. FAU - Du, Changlin AU - Du C AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Xu, Chuanting AU - Xu C AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Jia, Pengcheng AU - Jia P AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Cai, Na AU - Cai N AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Zhang, Zhenming AU - Zhang Z AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Meng, Wenna AU - Meng W AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Chen, Lu AU - Chen L AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Zhou, Zhongnan AU - Zhou Z AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Wang, Qi AU - Wang Q AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Feng, Rui AU - Feng R AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Li, Jun AU - Li J AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Meng, Xiaoming AU - Meng X AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Huang, Cheng AU - Huang C AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. FAU - Ma, Taotao AU - Ma T AUID- ORCID: 0000-0003-2208-2505 AD - Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China. LA - eng GR - Natural Science Foundation of Anhui Province(2008085MH273)/Department of Science and Technology of Anhui Province/ GR - Anhui Fund for Distinguished Young Scholars(2022AH020050)/Department of Science and Technology of Anhui Province/ GR - Research Fund of Anhui Institute of translational medicine(2022zhyx-B07)/Anhui Medical University/ GR - Research Fund of Anhui Institute of translational medicine(2021zhyx-B06)/Anhui Medical University/ GR - Scientific Research Promotion Fund of Anhui Medical University （2022xkjT010）/Anhui Medical University/ GR - Scientific Research Platform Improvement Project of Anhui Medical University (2023xkjT049)/Anhui Medical University/ GR - Scientific Research Promotion Fund of Anhui Medical University （2022xkjT010）/Anhui Medical University/ PT - Journal Article DEP - 20240205 PL - England TA - Elife JT - eLife JID - 101579614 RN - 94218WFP5T (aristolochic acid I) RN - 0 (NF-kappa B) RN - 0 (Interleukins) RN - 0 (Aristolochic Acids) SB - IM UOF - doi: 10.1101/2023.07.24.550330 MH - Animals MH - Mice MH - *Extracellular Traps MH - NF-kappa B MH - *Acute Kidney Injury/chemically induced MH - Interleukins MH - *Aristolochic Acids PMC - PMC10906995 OAB - Aristolochic acid nephropathy (or AAN for short) is a serious condition affecting the kidneys that is caused by certain traditional Chinese medicines containing a compound called aristolochic acid. This compound is known to have harmful effects on kidney tubular epithelial cells, causing increased inflammation and a form of controlled cell death called apoptosis, which can ultimately lead to organ failure. There is currently no effective treatment for AAN, highlighting the need for a deeper understanding of the mechanisms responsible. Previous studies have shown that immune cells called neutrophils infiltrate the kidneys and damage cells in the early stages of AAN. Neutrophils produce web-like structures called neutrophil extracellular traps, which have been identified as potentially contributing to the damage. A protein called PSTPIP2, which regulates inflammation, has also been shown to contribute to other types of kidney injury. To understand how these inflammatory factors might be involved in AAN, Du, Xu et al. genetically engineered mice to produce extra PSTPIP2 protein specifically in their kidneys. When given aristolochic acid, these mice displayed less kidney damage. Further studies of mouse kidney cells showed that PSTPIP2 protects the kidney by suppressing an inflammatory mechanism that leads to the production of neutrophil extracellular traps. By contrast, in models where PSTPIP2 levels were reduced, neutrophil extracellular traps were shown to cause both apoptosis and kidney injury. The findings of Du, Xu et al. show that neutrophil extracellular traps cause cell damage and apoptosis in a mouse model of AAN and that this action can be reduced by increasing the levels of the protein PSTPIP2. This sheds light on the inflammatory mechanisms behind the kidney damage caused by herbal medicines containing aristolochic acid. Additionally, it opens new avenues for studies aiming to find ways to treat AAN, suggesting that targeting PSTPIP2 could be a promising strategy. OABL- eng OTO - NOTNLM OT - cell biology OT - human OT - immunology OT - inflammation OT - kidney OT - medicine OT - mouse COIS- CD, CX, PJ, NC, ZZ, WM, LC, ZZ, QW, RF, JL, XM, CH, TM No competing interests declared EDAT- 2024/02/05 14:44 MHDA- 2024/03/04 06:43 PMCR- 2024/02/05 CRDT- 2024/02/05 08:48 PHST- 2023/05/29 00:00 [received] PHST- 2024/02/04 00:00 [accepted] PHST- 2024/03/04 06:43 [medline] PHST- 2024/02/05 14:44 [pubmed] PHST- 2024/02/05 08:48 [entrez] PHST- 2024/02/05 00:00 [pmc-release] AID - 89740 [pii] AID - 10.7554/eLife.89740 [doi] PST - epublish SO - Elife. 2024 Feb 5;13:e89740. doi: 10.7554/eLife.89740.