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

被引：6

作者：

Doute, Melodie ^{[1
,2
,3
]}

Sannier, Aurelie ^{[1
,2
,4
]}

Even, Guillaume ^{[1
,2
]}

Tran, Thi-Thu ^{[1
,2
]}

Gaston, Ahn-Tu ^{[1
,2
]}

Delbosc, Sandrine ^{[1
,2
]}

Loyau, Stephane ^{[1
,2
]}

Bruneval, Patrick ^{[5
,6
]}

Witko-Sarsat, Veronique ^{[3
,7
]}

Mouthon, Luc ^{[3
,7
,8
,9
]}

Nicoletti, Antonino ^{[1
,2
,3
]}

Caligiuri, Giuseppina ^{[1
,2
,3
,10
]}

Clement, Marc ^{[1
,2
,3
,11
]}

机构：

[1] Univ Paris Cite, Paris, France

[2] Univ Sorbonne Paris Nord, Lab Vasc Sci LVTS, INSERM U1148, Paris, France

[3] Lab Excellence INFLAMEX, Paris, France

[4] Univ Paris, Hop Bichat, Assistance Publ Hop Paris AP HP, Serv Anat & Cytol Pathol, Paris, France

[5] Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Nephrol, Paris, France

[6] Hop Europeen Georges Pompidou, Assistance Publ Hop Paris, Dept Pathol, Paris, France

[7] Univ Paris, Inst Cochin, INSERM U1016, CNRS UMR 8104, Paris, France

[8] Hop Cochin, Assistance Publ Hop Paris AP HP, Ctr Reference Malad Autoimmunes Syst Rares Ile Fra, Serv Med Interne, Paris, France

[9] Univ Paris Coyr, Hop Cochin, Assistance Publ Hop Paris AP HP, CUP, Paris, France

[10] Hop Univ Paris Nord Val de Seine, Assistance Publ Hop Paris, Dept Cardiol, Sote Bichat, Paris, France

[11] Lab Vasc Sci LVTS, Team Cardiovasc Immunobiol 1, INSERM U1148, 46 Rue Henri Huchard, F-75018 Paris, France

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2023年 / 34卷 / 07期

关键词：

TGF-BETA; INFLAMED GLOMERULUS; C-MPL; KIDNEY; RECRUITMENT; IL-1-ALPHA; PLATELETS; FIBROSIS;

D O I：

10.1681/ASN.0000000000000127

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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, TGFb-dependent glomerulosclerosis, and microvascular rarefaction. In humans, extracapillary glomerulonephritis is associated with thromboinflammation, TGFb-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.

引用

页码：1207 / 1221

页数：15

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