Mesangial cell hypercellularity and iron accumulation in the kidney associated with administration of a sickle hemoglobin modulator in CD-1 mice

The kidney plays an important role in iron homeostasis and mesangial cells (MCs) are phagocytic cells important for glomerular homeostasis. Sickle hemoglobin (HbS) modulators are promising clinical candidates for treatment of sickle cell disease. Although they prevent disease pathophysiology of HbS polymerization and red blood cell (RBC) sickling by increasing hemoglobin oxygen affinity, higher oxygen affinity can also cause transient tissue hypoxia with compensatory increases in erythropoiesis and subsequent increases in RBC turnover. CD-1 mice treated with an HbS modulator for 2 weeks developed higher RBC mass, increased erythropoiesis, and, by 1 month, deposition of intracellular pigments in renal tubular and parietal epithelium. In addition, in mice treated for 26 weeks, pigment was observed in MCs, which was accompanied by glomerular cell aggregates (MC hypercellularity) and tubulo-interstitial inflammation. The pigment was confirmed by Perl's iron staining and transmission electron microscopy (TEM) to be iron-containing proteins. Glomerular cell aggregates were confirmed to be MCs by TEM, and Ki-67 immunolabeling suggested that MC hypercellularity was due to proliferation. Collectively, these findings, along with iron-containing proteins in livers and spleens, suggested that iron overload secondary to increased RBC turnover led to increased renal iron reabsorption. While both MC hypercellularity and tubulo-interstitial inflammation were thought to be responses to long-term accumulation of iron, the former was considered a homeostatic response to eliminate iron, and maintain glomerular structure and function, while the latter was more consistent with an iron-catalyzed oxidative stress response. To our knowledge, this is the first report of MC hypercellularity in a preclinical toxicity study.