Kidney Week

Abstract: SA-OR017

Hepcidin Mitigates Sepsis-Induced AKI through Its Antibacterial and Anti-Inflammatory Effects

Session Information

• AKI: Inflammation and Regeneration
  October 27, 2018 | Location: 6B, San Diego Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Scindia, Yogesh M., Univerisity of Virginia, Charlottesville, Virginia, United States

Yogesh M. Scindia, PhD



Unraveling the role of iron metabolism in acute kidney injury (AKI), lupus nephritis (LN) and candidiasis My studies at have identified a protective role of “hepcidin”, the master regulator of iron metabolism in renal ischemia reperfusion injury (IRI) and septic AKI. These studies have established iron mediated immune regulation as an important therapeutic target in ischemic and septic AKI. Additionally, my new studies have for the first time identified exogenous hepcidin as an intervention to delay the onset and mitigate lupus nephritis by inhibiting macrophage and lymphocyte inflammatory response and proliferation, independent of renal immune complexes, thus B cells. Previously, I have identified early events (during asymptomatic stage of LN) that lead to mesangial cell antigen specific T cells recruitment to the kidney to initiate glomerulonephritis, and susceptibility genes in development of SLE LN. My current studies at University of Florida focus on further understanding role of iron, hepcidin in autoimmune kidney diseases and disseminating candidiasis.

• Mandziak, Ewa U., University of Virginia, Charlottesville, Virginia, United States

Ewa U. Mandziak,

• Leeds, Joseph T., University of Virginia, Charlottesville, Virginia, United States

Joseph T. Leeds,

• Loi, Valentina, AO Brotzu Cagliari, Cagliari, Italy

Valentina Loi,

• Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States

Sundararaman Swaminathan,

Background

Sepsis-induced acute kidney injury (AKI) is a common cause of in-hospital morbidity and mortality. Sepsis induces hepcidin-dependent iron sequestration to limit iron availability to pathogens. Hepcidin can limit inflammation. Therefore, we investigated if hepcidin pretreatment would mitigate endotoxin- and peritonitis-induced systemic pathology and AKI.

Methods

C57BL/6 mice were treated with saline or 50 μg hepcidin, 24 hours before LPS injection (Escherichia coli O111:B4, 6.5 mg/kg) or subjected to Cecal ligation and puncture (CLP) to induce peritonitis. Some mice underwent splenectomy (SPLX) and were challenged with LPS, with and without Hepcidin. Mice undergoing CLP received another dose of hepcidin, 2 hours prior to CLP. Renal injury and inflammatory markers were assessed. After CLP, mice were euthanized at different time points. Mouse macrophages (J774A) were treated with SiRNA to H-ferritin or scramble, treated with 1μg/mL Hepcidin for 4 hours,and cultured with 1 ng/mL LPS for 6 hours.

Results

LPS-induced AKI (plasma creatinine, renal NGAL and KIM-1 gene expression) were significantly reduced by hepcidin pretreatment. Hepcidin also reduced LPS-induced renal Cox-2, loss in PGC1a and enzymatic activity of cytochrome c oxidase. Hepcidin induced higher splenic H-ferritin, reduced splenocytes apoptosis, and inflammation. SPLX reduced LPS-induced AKI, and hepcidin did not provide additional protection in these settings. In CLP model, Hepcidin significantly reduced bacteremia, AKI, and mortality (colony forming units in the blood, renal NGAL and KIM-1 gene expression) and increased survival (up to 6 days in hepcidin-treated mice compared to approximately 24 hrs in PBS-treated mice). Compared to scramble siRNA, H-ferritin-deficient macrophages treated with Hepcidin secreted more LPS-induced IL-6.

Conclusion

Our results demonstrate a protective role of hepcidin in endotoxin- and peritonitis-induced pathologies and AKI, exerted through H-ferritin-dependent anti-inflammatory effects, and antibacterial property. Splenectomy protects against LPS-induced AKI.

Funding

• NIDDK Support