Impact of renal iron overload on sickle cell nephropathy in a humanized mouse model

Increased morbidity and mortality are associated with iron overload in sickle cell disease (SCD). Renal iron accumulation, a direct consequence of intravascular hemolysis, occurs in both patients and murine model of SCD, and correlates with albuminuria, an early marker of kidney injury. We aimed to investigate the role of kidney-specific iron accumulation and underlying mechanisms contributing to iron overload-mediated SCD nephropathy in humanized sickle cell disease (HbSS) mice. In addition, as sex differences in renal phenotype exist, we examined sex disparities in iron-associated toxicity in murine SCD. Iron chelation significantly reduced renal iron accumulation and subsequently prevented a decline in kidney function and disease progression only in male HbSS mice. Examining the mechanisms of kidney injury, secondary to renal iron accumulation, revealed the presence of oxidative stress and concurrent absence of ferroptosis in HbSS mice. In addition, the proximal tubule from HbSS male mice had reduced basal mitochondrial respiration compared with HbSS female mice. Iron chelation had no effect on any of the tested injury-mediated pathways but did reduce proinflammatory signature in the kidneys of HbSS mice. These results demonstrate that iron chelation exerts nephroprotective effects in male HbSS mice, whereas enhanced mitochondrial quality in HbSS female may account, at least in part, for potential sex differences in SCD nephropathy.NEW & NOTEWORTHY SCD, an inherited hemolytic anemia, is associated with increased mortality from prolonged iron overload. Current interventional strategies are limited to the chelation of transfusion-mediated iron overload only, leaving kidney-specific, hemolysis-driven iron burden unaddressed. This study provided preclinical evidence that iron chelation prevents kidney-specific iron overload and subsequent kidney injury in a murine model of SCD. Thus, iron chelation of systemic- and transfusion-independent renal iron accumulation may slow the progression of SCD nephropathy.