Faculty Bibliography

INTRODUCTION/BACKGROUND:Ischemic acute kidney injury (AKI) frequently occurs in the intensive care unit. However, early diagnosis is challenging, and specific treatment strategies are still lacking. Here, our study identified endogenous hepcidin was induced with increasing severity of ischemia/reperfusion (I/R) injury mostly in collecting duct (CD) principal and intercalated cells. METHODS:We employed RNA sequencing, immunoprecipitation, mass spectrometry, and gene knockdown and knockin technologies to define the role of hepcidin during I/R-induced kidney injury. RESULTS:Mechanically, RNA seq revealed hepcidin protected M-1 cells (murine cortical CD cell line) against ferroptosis following hypoxia/reoxygenation (H/R). Furthermore, immunoprecipitation-mass spectrometry identified hepcidin interacting with lactoferrin, consequently preserving the expression of lactoferrin following H/R which mediated the protective effect of hepcidin. Correspondingly, lactoferrin knockdown reduced the anti-ferroptotic effect of hepcidin in M-1 cells exposed to H/R revealing a novel function of hepcidin independent of the iron transporter ferroportin. In vivo, utilizing CD-specific hepcidin-knockin (HepcidinKspKI) and CD-specific hepcidin-knockdown mice (Adeno Associated Virus-Hep), we found that endogenous hepcidin protected against CD ferroptosis by preserving lactoferrin which consequently mitigated ischemic kidney injury and dysfunction, remarkedly improving the survival rate. Finally, recombinant hepcidin administration exhibited a comparable protective effect, albeit with less efficacy in reducing the mortality rate compared to conditional knockin of CD hepcidin. CONCLUSION/CONCLUSIONS:Collectively, our study identified an endogenous protective mechanism of injured CD cells via a hepcidin/lactoferrin/ferroptosis axis which may suggest a novel pharmacologic therapeutic for ischemic AKI.

SARS-CoV-2 vaccines have unquestionably blunted the overall impact of the COVID-19 pandemic, but host factors such as age, sex, obesity, and other co-morbidities can affect vaccine efficacy. We identified individuals in a relatively healthy population of healthcare workers (CORALE study cohort) who had unexpectedly low peak anti-spike receptor binding domain (S-RBD) antibody levels after receiving the BNT162b2 vaccine. Compared to matched controls, "low responders" had fewer spike-specific antibody-producing B cells after the second and third/booster doses. Moreover, their spike-specific T cell receptor (TCR) repertoire had less depth and their CD4⁺ and CD8⁺T cell responses to spike peptide stimulation were less robust. Single cell transcriptomic evaluation of peripheral blood mononuclear cells revealed activation of aging pathways in low responder B and CD4⁺T cells that could underlie their attenuated anti-S-RBD antibody production. Premature lymphocyte aging may therefore contribute to a less effective humoral response and could reduce vaccination efficacy.