Circulating FH Protects Kidneys From Tubular Injury During Systemic Hemolysis

Abstract

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.

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

“…This intrarenal complement activation could be due to the local overexpression of C3, as described in lupus nephritis 27 and in graft rejection, 28,29 and/or mediated by the systemic C3 as in I/R 30 or hemolysis-induced renal injury. 12 Since glycerol-injected mice with plasma C3 consumption (FHhepato-/-and CVF-treated mice) were protected from complement activation, the major role was played by the systemic C3.…”

“…Moreover, the overexpression of C5aR1 on tubular cells, together with its increase on macrophages could contribute to the AKI, as described in renal I/R injury 43,44 and hemolysis. 12 Evaluation of C5a in urine of human and murine RIAKI could be a potential future biomarker, as urine C5a has been associated with AKI. 45 Interestingly, we found no tubular C5b-9 deposits in mice or in humans, contrary to previous report in rat RIAKI.…”

“…10 However, complement overactivation is implicated in diseases affecting kidneys and/or associated with heme release. 11,12 Indeed, cell-free heme activates the alternative pathway. 13 Moreover, complement is pathogenic in ischemia-reperfusion injury (I/R).…”

Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

“…However, other studies suggest that despite elevated HO-1 expression, renal alterations in this model are at least partly independent of heme, since injection of free heme could not reproduce them and administration of the heme scavenger hemopexin could not prevent them in the PHZ model [115]. If complement overactivation in PHZ-induced hemolysis is involved in tissue damage [118], HO-1 expression seems to be independent of it, despite the kidney injury phenotype, since expression of HO-1 was comparable in wild type (WT) and C3 −/− , PHZ-treated [118] and factor H (FH)-pretreated mice [119]. Therefore, HO-1 expression appears to be dependent on hemolytic status rather than complement-mediated tubular injury [119], and hemopexin prevented complement activation in the PHZ model without affecting HO-1 expression [120].…”

“…If complement overactivation in PHZ-induced hemolysis is involved in tissue damage [118], HO-1 expression seems to be independent of it, despite the kidney injury phenotype, since expression of HO-1 was comparable in wild type (WT) and C3 −/− , PHZ-treated [118] and factor H (FH)-pretreated mice [119]. Therefore, HO-1 expression appears to be dependent on hemolytic status rather than complement-mediated tubular injury [119], and hemopexin prevented complement activation in the PHZ model without affecting HO-1 expression [120]. Thus HO-1 in the PHZ model protects the kidney from heme-dependent renal alterations, probably without influencing complement activation or other heme-independent injuries.…”