Acute kidney injury (AKI) is a major cause of mortality. There are no FDA-approved drugs to prevent or treat AKI. Low urine hepcidin levels predict AKI. Hepcidin downregulates ferroportin (FP) and induces tissue protective H-ferritin to reduce free intracellular iron. Hepcidin mimetics (minihepcidin/PR-73) are under development to treat iron overload disorders. Suberoylanilide hydroxamic acid (SAHA, Vorinostat), a FDA approved oral drug, is a potent inducer of hepcidin. Our preliminary data show that: 1) PR-73 and SAHA are protective against ischemia-reperfusion injury (IRI). 2) HepcidinKO mice display more severe kidney injury after IRI but are protected when pre-treated with hepcidin. 3) Hepcidin is also protective in other models of AKI. 4) Hepcidin reduces epithelial apoptosis, lipid peroxidation and macrophage infiltration in renal IRI. Macrophages and renal tubular epithelia express FP. We hypothesize that PR-73 or SAHA induces protection in IRI through FP and intracellular iron-dependent mechanisms that defend against epithelial injury and inflammation.
In Aim 1, we will establish the efficacy of novel hepcidin mimetics and hepcidin inducers in AKI.
In Aim 2, utilizing bone marrow chimeras and mice with macrophage or tubular epithelial FP deletion, we will determine if myeloid and/or epithelial FP downregulation is central for protection against IRI.
In Aim 3, we will examine novel cellular iron-dependent pathways that mediate hepcidin's protective effects- macrophage tristetraprolin and epithelial ferroptosis. Our studies will provide leads to identify novel small molecules to target FP, ferroptosis and tristetraprolin in the prevention of AKI that may ultimately lead to human AKI clinical trials.
Acute kidney injury (AKI) is associated with high mortality. Since, there are no FDA-approved drugs available to prevent or treat AKI, there is compelling reason to identify novel drugs. In this proposal, we examine the utility of drugs that target iron metabolism as a novel strategy in the prevention of AKI.
| Swaminathan, Sundararaman (2018) Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury. Nephron 140:156-159 |
| Swaminathan, Sundararaman (2016) Gadolinium toxicity: Iron and ferroportin as central targets. Magn Reson Imaging 34:1373-1376 |
| Charlton, Jennifer R; Pearl, Valeria M; Denotti, Anna R et al. (2016) Biocompatibility of ferritin-based nanoparticles as targeted MRI contrast agents. Nanomedicine 12:1735-45 |
