Contribution of myeloid HO-1 to the modulation of renal ischemia-reperfusion injury

Contribution of myeloid HO-1 to the modulation of

renal ischemia-reperfusion injury

Effect of myeloid HO-1 induction with hemin as a preemptive treatment

strategy against renal ischemia-reperfusion injury

Thesis submitted by Maxime ROSSI, MD

in fulfilment of the requirements of the PhD Degree in “Docteur en Sciences Médicales”

Academic year 2020-2021

Supervisor: Professor Alain Le Moine

Co-supervisor: Professor Véronique Flamand

Institute for Medical Immunology

Thesis jury:

Pr Michel Braun (Université libre de Bruxelles, Chair)

Pr Alain Le Moine (Université libre de Bruxelles, Secretary)

Pr Véronique Flamand (Université libre de Bruxelles)

Pr Xavier De Deken (Université libre de Bruxelles)

Pr Khalid Ismaili (Hôpital universitaire des enfants Reine Fabiola)

Pr Basile Stamatopoulos (Université libre de Bruxelles)

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Table of contents

REMERCIEMENTS ... - 3 -

LIST OF FIGURES ... - 6 -

LIST OF TABLES ... - 8 -

ABSTRACT ... - 9 -

RESUME ... - 11 -

ABBREVIATIONS ... - 14 -

INTRODUCTION ... - 19 -

I. Kidney: a brief overview ... - 19 -

1. Basic anatomy ...- 19 -

1.1 Location ...- 19 -

1.2 Microscopic anatomy ...- 20 -

1.3 Collecting system ...- 20 -

1.4 Blood supply and microvascularisation ...- 21 -

2. Comparative kidney anatomy ...- 23 -

II. Ischemia-reperfusion injury (IRI) and kidney ... - 24 -

1. Presentation ...- 24 -

2. IRI and acute kidney injury (AKI) ...- 25 -

3. Physiopathology of IRI-induced AKI ...- 28 -

3.1 Endothelial and microvascular dysfunctions in ischemic AKI ...- 29 -

3.2 Immune response in ischemic AKI ...- 33 -

3.2.1 Tubular cells and inflammation in ischemic AKI ...- 34 -

3.2.2 Myeloid cells in ischemic AKI ...- 36 -

3.2.2.1 Neutrophils in ischemic AKI ...- 37 -

3.2.2.2 Monocytes/Macrophages in ischemic AKI ...- 37 -

3.2.2.3 Dendritic cells in ischemic AKI ...- 45 -

4. Adaptive repair after IRI-induced AKI ...- 46 -

5. Maladaptive repair after IRI-induced AKI ...- 48 -

5.1 Maladaptive repair and cell cycle arrest...- 49 -

5.2 Maladaptive repair and autophagy disruption...- 50 -

5.3 Maladaptive repair and macrophages ...- 51 -

5.4 Origins of myofibroblasts in renal fibrosis ...- 51 -

5.4.1 Bone marrow-derived fibrocytes ...- 52 -

5.4.2 Epithelial-mesenchymal transition (EMT)...- 53 -

5.4.3 Renal pericytes ...- 53 -

5.4.4 Macrophage-to-myofibroblast transition (MMT) ...- 53 -

6. Remote organ damage in IRI-induced AKI...- 54 -

6.1 Kidney-liver cross-talk ...- 55 -

6.2 Kidney-heart cross-talk ...- 55 -

6.3 Kidney-brain cross-talk ...- 55 -

6.4 Kidney-intestine cross-talk ...- 56 -

6.5 Kidney-lung cross-talk ...- 56 -

III. Heme oxygenase-1 (HO-1) ... - 57 -

1. Presentation ...- 57 -

2. Tissue expression ...- 58 -

3. Subcellular localization ...- 58 -

4. Genetics and regulation of HO-1 expression ...- 59 -

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4.2 Hmox1 deletion ...- 60 -

4.3 Hmox1 promoter polymorphisms ...- 61 -

4.4 Regulation of Hmox1 gene expression ...- 61 -

4.4.1 Transcriptional factors ...- 61 -

4.4.2 Signaling cascades ...- 63 -

4.4.3 MicroRNAs ...- 64 -

5. Modulation of HO-1 expression ...- 64 -

5.1 Natural HO-1-inducing compounds ...- 64 -

5.2 Pharmaceutical HO-1-inducing compounds ...- 65 -

5.3 Cell-derived HO-1-inducing mediators ...- 65 -

5.4 Heavy metals HO-1-inducing compounds ...- 65 -

6. Cytoprotective effects of HO-1 ...- 66 -

6.1 Antioxidant effect of HO-1...- 66 -

6.2 Antiapoptotic effect of HO-1 ...- 67 -

7. Effects of HO-1 on immune system ...- 68 -

7.1 Anti-inflammatory effect of HO-1 ...- 68 -

7.2 HO-1 and macrophage polarization ...- 70 -

8. HO-1 and renal IRI ...- 70 -

AIM OF THE WORK ... - 72 -

RESULTS ... - 73 -

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2.

3.

DISCUSSION ... - 76 -

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2.

2.1

2.2

3.

4.

5.

6.

PERSPECTIVES ... - 86 -

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2.

3.

4.

CONCLUSIONS ... - 89 -

MATERIALS AND METHODS ... - 91 -

REFERENCES ... - 98 -