Renal cortical hemopexin accumulation in response to acute kidney injury

Zager RA, Johnson AC, Becker K. Renal cortical hemopexin accumulation in response to acute kidney injury. Am J Physiol Renal Physiol 303: F1460-F1472, 2012. First published September 19, 2012; doi:10.1152/ajprenal.00426.2012.-Hemopexin (Hpx) is a liver-generated acute phase reactant that binds and neutralizes prooxidant free heme. This study tested whether acute kidney injury (AKI) triggers renal Hpx accumulation, potentially impacting heme Femediated tubular injury. Mice were subjected to glycerol, cisplatin, ischemia-reperfusion (I/R), or endotoxemic [lipopolysaccharide (LPS)] AKI. In each instance, 3- to 30-fold renal cortical and isolated proximal tubule segment (PTS) Hpx increases resulted. Although renal cortex and PTS showed variable Hpx mRNA increases, due, in part, to increased mRNA stability, mRNA levels did not correlate with renal Hpx protein accumulation. Conversely, AKI evoked three-to fourfold increases in hepatic Hpx gene induction, which corresponded with three-to fourfold plasma Hpx increases. Renal immunohistochemistry, and increased urinary Hpx excretion, indicated that circulating Hpx gains tubule luminal/urinary access, followed by proximal tubule endocytic uptake. Paradoxically, in cultured renal cells (HK-2, HEK-293), Fe depletion, and not free heme excess, increased Hpx mRNA. LPS acutely increased HK-2 cell Hpx mRNA. This finding, coupled with observations that LPS evoked similar to 30-fold greater renal Hpx mRNA increases than any other AKI model, suggests that inflammation, not heme exposure, activates the renal Hpx gene. Each form of AKI evoked early increases in circulating free heme, which subsequently fell to subnormal levels as plasma Hpx rose. In addition, purified Hpx blunted free Fe-mediated HK-2 cell death. In sum, these data indicated that AKI-associated hepatic stress generates Hpx, which gains renal tubule access. Given its ability to bind free heme and mitigate free Fe toxicity, Hpx loading can potentially confer cytoprotective effects.