Iron-mediated oxidative stress is implicated in the pathogenesis of renal ischemia-reperfusion injury. Hepcidin is an endogenous acute phase hepatic hormone that prevents iron export from cells by inducing degradation of the only known iron export protein, ferroportin. In this study, we used a mouse model to investigate the effect of renal ischemia-reperfusion injury on systemic iron homeostasis and determine if dynamic modulation of iron homeostasis with hepcidin has therapeutic benefit in the treatment of AKI. Renal ischemia-reperfusion injury induced hepatosplenic iron export through increased ferroportin expression, which resulted in hepatosplenic iron depletion and an increase in serum and kidney nonheme iron levels. Exogenous hepcidin treatment prevented renal ischemia-reperfusion-induced changes in iron homeostasis. Hepcidin also decreased kidney ferroportin expression and increased the expression of cytoprotective H-ferritin. Hepcidininduced restoration of iron homeostasis was accompanied by a significant reduction in ischemia-reperfusioninduced tubular injury, apoptosis, renal oxidative stress, and inflammatory cell infiltration. Hepcidin-deficient mice demonstrated increased susceptibility to ischemia-reperfusion injury compared with wild-type mice. Reconstituting hepcidin-deficient mice with exogenous hepcidin induced hepatic iron sequestration, attenuated the reduction in renal H-ferritin and reduced renal oxidative stress, apoptosis, inflammation, and tubular injury. Hepcidin-mediated protection was associated with reduced serum IL-6 levels. In summary, renal ischemiareperfusion injury results in profound alterations in systemic iron homeostasis. Hepcidin treatment restores iron homeostasis and reduces inflammation to mediate protection in renal ischemia-reperfusion injury, suggesting that hepcidin-ferroportin pathway holds promise as a novel therapeutic target in the treatment of AKI.

Background:  Recent studies have demonstrated the expression of Toll‐like receptor 3 (TLR3) in salivary glands and epithelial cell lines derived from Sjögren’s syndrome (SS) patients. As viral infections are considered to be a trigger for SS, in this study we investigated whether in vivo engagement of TLR3 affects salivary gland function. Methods:  Female New Zealand Black/WF1 mice were repeatedly injected with polyinosinic:polycytidylic acid [poly(I:C)]. TLR3 expression within submandibular glands was studied using immunohistochemistry. RNA levels of inflammatory cytokines in the submandibular glands were determined by real time polymerase chain reaction. Pilocarpine induced saliva volume was used as an index of glandular function. Results:  Immunohistochemical analysis of submandibular glands showed TLR3 expression in epithelium of serous and mucous acini, granular convoluted tubules, and ducts. Poly(I:C) treatment rapidly up‐regulated the mRNA levels of type I interferon (IFN) and inflammatory cytokines in the submandibular glands. One week after treatment, the saliva volumes in poly(I:C) treated mice were significantly reduced in comparison with the phosphate‐buffered saline (PBS) treated mice. Hematoxylin and eosin staining showed that salivary gland histology was normal and lymphocytic foci were not detected. Glandular function recovered after poly(I:C) treatment was stopped. Conclusions:  Our results demonstrate that engagement of TLR3 within the salivary glands results in a rapid loss of glandular function. This phenomenon is associated with the production of type I IFN and inflammatory cytokines in the salivary glands. Restoration of glandular function suggests that for viral etiology of SS, a chronic infection of salivary glands might be necessary.

The glomerulus is the filtration unit of the kidney. Disruption of glomerular function may be caused by primary glomerular pathology or secondary to systemic diseases. The mesangial, endothelial and epithelial cells of the glomerulus are involved in most pathologic processes. Animal models provide an understanding of the molecular basis of glomerular disease. These studies show that mesangial cells are critical players in initiation and progression of disease. Therefore, modulation of mesangial cell responses offers a novel therapeutic approach. The complex architecture of the kidney, specifically the renal glomerulus makes targeted drug delivery especially challenging. Targeted delivery of therapeutic agents reduces dose of administration and minimizes unwanted side effects caused by toxicity to other tissues. The currently available modalities demonstrating the feasibility of mesangial cell targeting are discussed.

Objective Sjögren’s syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. The current study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of Sjögren’s syndrome-like disease. Methods Female New Zealand Black × New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland infiltrating cells were characterized by flow cytometry. Results Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C) treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates and these were followed by CD4+ T cells. Conclusions Our data clearly demonstrates that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for Sjögren’s syndrome-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of Sjögren’s syndrome.

Iron is required for key aspects of cellular physiology including mitochondrial function and DNA synthesis and repair. However, free iron is an aberration because of its ability to donate electrons, reduce oxygen, and generate reactive oxygen species. Iron-mediated cell injury or ferroptosis is a central player in the pathogenesis of acute kidney injury. There are several homeostatic proteins and pathways that maintain critical balance in iron homeostasis to allow iron's biologic functions yet avoid ferroptosis. Hepcidin serves as the master regulator of iron homeostasis through its ability to regulate ferroportin-mediated iron export and intracellular H-ferritin levels. Hepcidin is a protective molecule in acute kidney injury. Drugs targeting hepcidin, H-ferritin, and ferroptosis pathways hold great promise to prevent or treat kidney injury. In this review we discuss iron homeostasis under physiological and pathologic conditions and highlight its importance in acute kidney injury. Semin Nephrol 39:76−84 Ó