Thrombopoietin-Dependent Myelo-Megakaryopoiesis Fuels Thromboinflammation and Worsens Antibody-Mediated Chronic Renal Microvascular Injury

Author:

Douté Mélodie12,Sannier Aurélie13,Even Guillaume1,Tran Thi-Thu1,Gaston Ahn-Tu1,Delbosc Sandrine1,Loyau Stéphane1,Bruneval Patrick4,Witko-Sarsat Véronique25,Mouthon Luc2567,Nicoletti Antonino12,Caligiuri Giuseppina128,Clement Marc12ORCID

Affiliation:

1. Université Paris Cité and Université Sorbonne Paris Nord, INSERM U1148, Laboratory for vascular science (LVTS), Paris, France

2. Laboratoire d'Excellence INFLAMEX, Paris, France

3. Université de Paris, Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'Anatomie et Cytologie Pathologiques, Hôpital Bichat, Paris, France

4. Departments of Nephrology Pathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

5. Université de Paris, INSERM U1016, CNRS UMR 8104, Institut Cochin, Paris, France

6. Service de Médecine Interne, Centre de Référence Maladies Autoimmunes Systémiques Rares d'Ile de France, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

7. Assistance Publique-Hôpitaux de Paris (AP-HP)-CUP-CUP, Hôpital Cochin, Université Paris Cité, Paris, France

8. Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val-de-Seine, Site Bichat, Paris, France

Abstract

Significance Statement Kidney-derived thrombopoietin (TPO) increases myeloid cell and platelet production during antibody-mediated chronic kidney disease (AMCKD) in a mouse model, exacerbating chronic thromobinflammation in microvessels. The effect is mirrored in patients with extracapillary glomerulonephritis associated with thromboinflammation, TGFβ-dependent glomerulosclerosis, and increased bioavailability of TPO. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases. Neutralization of TPO in mice normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. The findings suggest that TPO is a relevant biomarker and a promising therapeutic target for patients with CKD and other chronic thromboinflammatory diseases. Background Chronic thromboinflammation provokes microvascular alterations and rarefaction, promoting organ dysfunction in individuals with various life-threatening diseases. Hematopoietic growth factors (HGFs) released by the affected organ may sustain emergency hematopoiesis and fuel the thromboinflammatory process. Methods Using a murine model of antibody-mediated chronic kidney disease (AMCKD) and pharmacological interventions, we comprehensively monitored the response to injury in the circulating blood, urine, bone marrow, and kidney. Results Experimental AMCKD was associated with chronic thromboinflammation and the production of HGFs, especially thrombopoietin (TPO), by the injured kidney, which stimulated and skewed hematopoiesis toward myelo-megakaryopoiesis. AMCKD was characterized by vascular and kidney dysfunction, TGFβ-dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGFβ-dependent glomerulosclerosis, and increased bioavailability of TPO. Analysis of albumin, HGF, and inflammatory cytokine levels in sera from patients with extracapillary glomerulonephritis allowed us to identify treatment responders. Strikingly, TPO neutralization in the experimental AMCKD model normalized hematopoiesis, reduced chronic thromboinflammation, and ameliorated renal disease. Conclusion TPO-skewed hematopoiesis exacerbates chronic thromboinflammation in microvessels and worsens AMCKD. TPO is both a relevant biomarker and a promising therapeutic target in humans with CKD and other chronic thromboinflammatory diseases.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Nephrology,General Medicine

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Kidney-Derived Thrombopoietin and Platelet Generation—A Proinflammatory Loop in CKD;Journal of the American Society of Nephrology;2023-05-22

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3