Abstract
Chronic kidney disease (CKD) is a worldwide public health problem affecting ~850 million people including 37
million Americans. Advanced CKD results in a number of adverse clinical outcomes leading to high rates of
mortality, morbidity, and healthcare expenditure. Recognizing these staggering challenges, the Department of
Health and Human Services initiated the “Advancing American Kidney Health (AAKH)” through Executive
Order in July 2019. Derangements in iron metabolism are a hallmark of advanced CKD, however, the
mechanistic underpinnings of such perturbations and their clinical impact on the course of CKD are not fully
understood. The overall goal of this project is to fill the current gaps in knowledge and address this unmet need
for the development of novel therapeutic interventions by targeting iron metabolism to slow progression of CKD
and delay the need for kidney replacement therapy, two of the major goals of the AAKH initiative. By
conducting preliminary studies, we have discovered that macrophage ferritin heavy chain (FtH) diminishes
development and progression of CKD. Guided by our findings we propose the unifying hypothesis that myeloid
FtH orchestrates iron distribution and regulates macrophage plasticity under injurious/inflammatory conditions.
This premise is substantiated by (i) significant upregulation of Spic, a lineage-defining transcription factor that
selectively controls development of iron recycling macrophages and (ii) marked elevation and aggregation of
synuclein-alpha (Snca), a common pro-inflammatory factor in neurodegenerative conditions in in two models of
CKD with substantially higher levels observed in kidneys of mice with targeted deletion of FtH in myeloid
compartment. To confirm our hypothesis, we will execute the following specific aims: Aim 1: To test the
hypothesis that myeloid FtH regulates monocyte/MF differentiation towards iron recycling phenotype through
controlling transcription factor Spic. Aim 2: To test the hypothesis that myeloid FtH establishes disease
tolerance to CKD via suppression of Snca. Successful completion of the proposed aims will have a significant
impact on our understanding of the individual and collective effects of myeloid FtH, Spic and Snca expression
in iron handling by the kidney and their detailed connotative roles in the pathogenesis of CKD, thereby paving
the way for a new therapeutic approach in this disease by targeting iron metabolism in CKD.