Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

Abstract

Moderate intravascular hemolysis is a common condition in newborns. It is followed by the accumulation of bilirubin, which is a secondary product of the activity of heme oxygenase-1, an enzyme that catalyzes the breakdown of heme released from disrupted erythrocytes and taken up by hepatic macrophages. Although these cells are a major site of enzymatic heme breakdown in adults, we show here that epithelial cells of proximal tubules in the kidneys perform the functions of both heme uptake and catabolism in mouse neonates. A time-course study examining mouse pups during the neonatal period showed a gradual recovery from hemolysis, and concomitant decreases in the expression of heme-related genes and non-heme iron transporters in the proximal tubules. By adjusting the expression of iron-handling proteins in response to the disappearance of hemolysis in mouse neonates, the kidneys may play a role in the detoxification of iron and contribute to its recirculation from the primary urine to the blood.

Exacerbation of Neonatal Hemolysis and Impaired Renal Iron Handling in Heme Oxygenase 1-Deficient Mice

“…In our previous study [ 13 ], we localized the HRG1 protein in apical/subapical regions of epithelial cells of the renal cortex in WT neonates, which suggested its participation in the uptake of free heme from primary urine under conditions of neonatal hemolysis. Here, we confirmed this localization in the kidneys of both WT and Hmox1 −/− mice ( Figure 4 a).…”

“…Recently, we determined a time-course of hemolysis in outbred mouse pups during the neonatal period [ 13 ]. Here, we confirmed those results using C57BL/6 × FVB mouse neonates.…”

“…We previously showed that, in the kidneys of WT mouse neonates, the expression of megalin and cubilin, involved in hemoglobin clearance in the renal proximal tubules [ 16 ], was transiently (between days 3 and 7 after birth) increased in the apical membrane of the epithelial cells of the renal proximal tubules [ 13 ]. Here, immunofluorescent (IF) co-localization studies of megalin and cubilin showed that the increased megalin–cubilin IF signal in the apical part of the cortical renal tubules in Hmox1 −/− neonates was shifted in time compared to control animals and fell on days 7–11 postpartum ( Figure 3 a,b).…”

“…The enhanced susceptibility of neonatal erythrocytes to increased oxidative stress is very likely the main reason of moderate intravascular hemolysis, which is a common, physiological condition in newborns. Interestingly, the course of neonatal hemolysis runs in parallel with developmentally impaired iron handling by liver macrophages [ 13 ]. Keeping all proportions, these phenomena are reminiscent of hemolytic events and macrophage dysfunction in HO1-deficient mice.…”

“…Keeping all proportions, these phenomena are reminiscent of hemolytic events and macrophage dysfunction in HO1-deficient mice. We have recently demonstrated that, in mouse neonates showing clear symptoms of hemolysis, the kidney is the primary organ involved in heme uptake and catabolism and, thus, contributes to its detoxification, as well as to heme-derived iron recirculation from the primary urine to the blood [ 13 ]. Moreover, we have shown that, apart from heme and iron transporters, HO1 is exclusively expressed in the renal cortex and plays a pivotal role in these processes.…”