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@article{Merle:2020:10.3389/fimmu.2020.01772,
author = {Merle, NS and Leon, J and Poillerat, V and Grunenwald, A and Boudhabhay, I and Knockaert, S and Robe-Rybkine, T and Torset, C and Pickering, MC and Chauvet, S and Fremeaux-Bacchi, V and Roumenina, LT},
doi = {10.3389/fimmu.2020.01772},
journal = {Frontiers in Immunology},
pages = {1--13},
title = {Circulating FH protects kidneys from tubular injury during systemic hemolysis},
url = {http://dx.doi.org/10.3389/fimmu.2020.01772},
volume = {11},
year = {2020}
}

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TY  - JOUR
AB  - 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
AU  - Merle,NS
AU  - Leon,J
AU  - Poillerat,V
AU  - Grunenwald,A
AU  - Boudhabhay,I
AU  - Knockaert,S
AU  - Robe-Rybkine,T
AU  - Torset,C
AU  - Pickering,MC
AU  - Chauvet,S
AU  - Fremeaux-Bacchi,V
AU  - Roumenina,LT
DO  - 10.3389/fimmu.2020.01772
EP  - 13
PY  - 2020///
SN  - 1664-3224
SP  - 1
TI  - Circulating FH protects kidneys from tubular injury during systemic hemolysis
T2  - Frontiers in Immunology
UR  - http://dx.doi.org/10.3389/fimmu.2020.01772
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000563382500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2020.01772/full
UR  - http://hdl.handle.net/10044/1/87713
VL  - 11
ER  -

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