Myeloid ferritins regulate injury and fibrosis following kidney ischemia reperfusion injury

Abstract

Acute kidney injury (AKI) is a major concern in critically ill patients due to its impact on morbidity and mortality. Pathogenesis of AKI is complex and involves oxidative stress, tubular cell death, impaired mitochondrial function, prolonged cell-cycle arrest and inflammation. Inflammatory cells, specifically, myeloid cells (neutrophils and macrophages) accumulate within the injured kidney and regulate response via cross-talk signaling with the kidney parenchyma. Ferritins are evolutionarily conserved proteins involved in iron metabolism. Intracellular ferritins exist as a shell, comprising of two subunits, ferritin heavy chain (FtH) and ferritin light chain (FtL). FtH is a ferroxidase that oxidizes ferrous iron to the ferric form, which is then stored within the shell. In recently published work, we demonstrated that ferritins are important regulators of oxidative stress and inflammation. We also identified that loss of one protein chain is associated with a compensatory increase in the other chain. Therefore, we generated new and unique transgenic mice with targeted deletion of both proteins in the myeloid compartment.The purpose of this study was to determine the effect of myeloid ferritins on kidney injury and repair following AKI. We characterized the newly generated double transgenic mice by examining the expression of ferritins in myeloid cells of the bone marrow and spleen. We confirmed deletion of ferritins from the myeloid compartment and this deletion was associated with reduced intracellular iron levels. In quiescence, we found no difference in kidney function between the knockout and floxed wildtype male mice. However, 24 hours after 19-minute bilateral kidney ischemia reperfusion injury (IRI), we found that wildtype mice had significantly higher loss of kidney function compared to knockout mice, as evidenced by rise in serum creatinine and reduction in GFR. Interestingly, this effect persisted until 14 days following reperfusion. At 28 days, we identified that myeloid ferritin deletion was associated with better preserved kidney architecture and lesser fibrotic remodeling, as evident by lower induction of collagen 1, α-smooth muscle actin and TGF-β. Compared to knockout mice, we found that wildtype mice had significantly higher expression of kidney injury marker-1 and VCAM-1, a marker of inflammatory proximal tubular cells. These studies suggest that myeloid ferritins mediate cross-talk signaling with the kidney tubular epithelium and dictate the trajectory of kidney injury. Current studies are aimed at elucidating the impact of myeloid ferritins on neutrophil and macrophage trafficking to the injured kidney and to determine the role of myeloid ferritins in regulating inflammation and cross-talk signaling with the tubular epithelium to regulate kidney injury and repair. Importantly, our findings suggest that modulation of ferritin expression during AKI has the potential of being a novel therapeutic modality. NIH R01 DK122986 to SB This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.