Acute kidney injury (AKI) is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has led to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress and inflammation as common pathogenic events. The kidney responds by prompt induction of its own antioxidant machinery including the highly inducible and anti-apoptotic heavy chain of the ferritin gene (FtH). FtH catalyzes the conversion of the reactive ferrous iron to ferric form thereby enabling safe sequestration of iron in the ferritin shell. Preliminary studies from our laboratory have shown that selective deletion of FtH in renal proximal tubules leads to increased structural and functional damage and macrophage accumulation following AKI. In addition, FtH expression in macrophages determines macrophage activation and polarization. The hypothesis of this proposal is that the cross talk between proximal tubules vs. macrophage FtH expression regulates the inflammatory response and the subsequent cascade of resolution of injury in response to IL-6, CSF-1 and MCP- 1.
In aim 1, the deleterious effects of proximal tubule specific FtH deletion on kidney injury and macrophage accumulation and polarization in AKI will be determined.
Aim 2 will test the hypothesis that FtH expression in macrophages will determine their potential to polarize towards distinct phenotypes and thereby regulate injury mediated cytotoxicity and fibrosis.
Aim 3 will test the hypothesis that FtH mediates the cross-talk between kidney and macrophages through modulation of signaling cascades that facilitate macrophage recruitment and polarization. Elucidating the inherent signaling pathways modulated by protective genes such as FtH in the kidney and macrophages and its contribution to injury or repair is integral in defining new treatment modalities in the reparative processes following AKI. This project will also provide an intensive research training program in macrophage biology and cell signaling in AKI under guidance of an experienced mentoring team allowing the applicant to develop and launch an independent career in academic nephrology.
The goals of this proposal are to determine the functional significance of ferritin expression in the kidney vs. the inflammatory cells in acute kidney injury The results of these studies will enable understanding the role for ferritin in the kidney-macrophage cross-talk and the consequential effects in mediating repair and may provide insight into novel means of intervention. These findings will also be applicable to other oxidative and inflammatory mediated diseases such as atherosclerosis and transplant rejection.