Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis
Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01772/full |
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| author | Nicolas S. Merle Juliette Leon Victoria Poillerat Anne Grunenwald Idris Boudhabhay Samantha Knockaert Tania Robe-Rybkine Carine Torset Matthew C. Pickering Sophie Chauvet Sophie Chauvet Veronique Fremeaux-Bacchi Veronique Fremeaux-Bacchi Lubka T. Roumenina |
| author_facet | Nicolas S. Merle Juliette Leon Victoria Poillerat Anne Grunenwald Idris Boudhabhay Samantha Knockaert Tania Robe-Rybkine Carine Torset Matthew C. Pickering Sophie Chauvet Sophie Chauvet Veronique Fremeaux-Bacchi Veronique Fremeaux-Bacchi Lubka T. Roumenina |
| author_sort | Nicolas S. Merle |
| collection | DOAJ |
| description | Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH−/−, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH−/− mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH−/− compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH−/− mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH−/− mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH−/− mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH−/− mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH−/− mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH−/− mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI. |
| first_indexed | 2024-12-21T19:38:34Z |
| format | Article |
| id | doaj.art-46b034fe48a84de9a00b0c1dc8408830 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T19:38:34Z |
| publishDate | 2020-08-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-46b034fe48a84de9a00b0c1dc84088302022-12-21T18:52:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.01772557583Circulating FH Protects Kidneys From Tubular Injury During Systemic HemolysisNicolas S. Merle0Juliette Leon1Victoria Poillerat2Anne Grunenwald3Idris Boudhabhay4Samantha Knockaert5Tania Robe-Rybkine6Carine Torset7Matthew C. Pickering8Sophie Chauvet9Sophie Chauvet10Veronique Fremeaux-Bacchi11Veronique Fremeaux-Bacchi12Lubka T. Roumenina13Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceCentre for Complement and Inflammation Research, Imperial College London, London, United KingdomCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceAssistance Publique – Hôpitaux de Paris, Service de Nephrologie, Hôpital Européen Georges Pompidou, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceAssistance Publique – Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, FranceIntravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH−/−, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH−/− mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH−/− compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH−/− mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH−/− mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH−/− mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH−/− mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH−/− mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH−/− mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.https://www.frontiersin.org/article/10.3389/fimmu.2020.01772/fullcomplement – immunological termcomplement factor Hhemolysiskidneyacute tubular damage |
| spellingShingle | Nicolas S. Merle Juliette Leon Victoria Poillerat Anne Grunenwald Idris Boudhabhay Samantha Knockaert Tania Robe-Rybkine Carine Torset Matthew C. Pickering Sophie Chauvet Sophie Chauvet Veronique Fremeaux-Bacchi Veronique Fremeaux-Bacchi Lubka T. Roumenina Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis Frontiers in Immunology complement – immunological term complement factor H hemolysis kidney acute tubular damage |
| title | Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis |
| title_full | Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis |
| title_fullStr | Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis |
| title_full_unstemmed | Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis |
| title_short | Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis |
| title_sort | circulating fh protects kidneys from tubular injury during systemic hemolysis |
| topic | complement – immunological term complement factor H hemolysis kidney acute tubular damage |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01772/full |
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