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2018 ; 9
(ä): 179
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Characterization of Renal Injury and Inflammation in an Experimental Model of
Intravascular Hemolysis
#MMPMID29545789
Merle NS
; Grunenwald A
; Figueres ML
; Chauvet S
; Daugan M
; Knockaert S
; Robe-Rybkine T
; Noe R
; May O
; Frimat M
; Brinkman N
; Gentinetta T
; Miescher S
; Houillier P
; Legros V
; Gonnet F
; Blanc-Brude OP
; Rabant M
; Daniel R
; Dimitrov JD
; Roumenina LT
Front Immunol
2018[]; 9
(ä): 179
PMID29545789
show ga
Intravascular erythrocyte destruction, accompanied by the release of
pro-oxidative and pro-inflammatory components hemoglobin and heme, is a common
event in the pathogenesis of numerous diseases with heterogeneous etiology and
clinical features. A frequent adverse effect related to massive hemolysis is the
renal injury and inflammation. Nevertheless, it is still unclear whether heme--a
danger-associated molecular pattern--and ligand for TLR4 or upstream
hemolysis-derived products are responsible for these effects. Well-characterized
animal models of hemolysis with kidney impairment are needed to investigate how
hemolysis drives kidney injury and to test novel therapeutic strategies. Here, we
characterized the pathological processes leading to acute kidney injury and
inflammation during massive intravascular hemolysis, using a mouse model of
phenylhydrazine (PHZ)-triggered erythrocyte destruction. We observed profound
changes in mRNA levels for markers of tubular damage (Kim-1, NGAL) and
regeneration (indirect marker of tubular injury, Ki-67), and tissue and vascular
inflammation (IL-6, E-selectin, P-selectin, ICAM-1) in kidneys of PHZ-treated
mice, associated with ultrastructural signs of tubular injury. Moreover, mass
spectrometry revealed presence of markers of tubular damage in urine, including
meprin-?, cytoskeletal keratins, ?-1-antitrypsin, and ?-1-microglobulin. Signs of
renal injury and inflammation rapidly resolved and the renal function was
preserved, despite major changes in metabolic parameters of PHZ-injected animals.
Mechanistically, renal alterations were largely heme-independent, since injection
of free heme could not reproduce them, and scavenging heme with hemopexin in
PHZ-administered mice could not prevent them. Reduced overall health status of
the mice suggested multiorgan involvement. We detected amylasemia and amylasuria,
two markers of acute pancreatitis. We also provide detailed characterization of
renal manifestations associated with acute intravascular hemolysis, which may be
mediated by hemolysis-derived products upstream of heme release. This analysis
provides a platform for further investigations of hemolytic diseases and
associated renal injury and the evaluation of novel therapeutic strategies that
target intravascular hemolysis.
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