Hepcidin as a Major Component of Renal Antibacterial Defenses against Uropathogenic Escherichia coli

Abstract

The iron-regulatory peptide hepcidin exhibits antimicrobial activity. Having previously shown hepcidin expression in the kidney, we addressed its role in urinary tract infection (UTI), which remains largely unknown. Experimental UTI was induced in wild-type (WT) and hepcidin-knockout (Hepc2/2) mice using the uropathogenic Escherichia coli CFT073 strain. Compared with infected WT mice, infected Hepc2/2 mice showed a dramatic increase in renal bacterial load. Moreover, bacterial invasion was significantly dampened by the pretreatment of WT mice with hepcidin. Infected Hepc2/2 mice exhibited decreased iron accumulation in the renal medulla and significant attenuation of the renal inflammatory response. Notably, we demonstrated in vitro bacteriostatic activity of hepcidin against CFT073. Furthermore, CFT073 repressed renal hepcidin, both in vivo and in cultured renal cells, and reduced phosphorylation of SMAD kinase in vivo, suggesting a bacterial strategy to escape the antimicrobial activities of hepcidin. In conclusion, we provide new mechanisms by which hepcidin contributes to renal host defense and suggest that targeting hepcidin offers a strategy to prevent bacterial invasion.

Renal Handling of Circulating and Renal-Synthesized Hepcidin and Its Protective Effects against Hemoglobin–Mediated Kidney Injury

“…Proximal tubules virtually do not synthesize hepcidin 15 but reabsorb filtered circulating hepcidin, whereas the distal tubules can synthesize hepcidin 14,15 but did not show uptake of the administered hhep25 in our studies. Interestingly, we observed that hhep25 injection in hemoglobin-treated mice led to a dramatic increase in renal Hamp1 mRNA expression and hepcidin immunostaining in the distal tubules.…”

“…1 Hepcidin has been shown to be synthesized in the mouse kidney, specifically in the distal nephron segment. 14,15 However, it is unclear whether this locally synthesized hepcidin is excreted in the urine. Other than uncertainties concerning the origin of urinary hepcidin during CABG, gaps exist in our common knowledge on renal hepcidin handling.…”

Predominant role of microglia in brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease

“…Hepcidin synthesis is also induced by inflammatory signals (such as IL‐6), and has a major role in the anemia associated with inflammation (Ganz, ). Although the liver is the major source of circulating hepcidin, the peptide is expressed (albeit to a lesser extent) by other organs (Coimbra, Catarino, & Santos‐Silva, ; Houamel et al, ; Qian et al, ; Wu et al, ). Interestingly, local hepcidin levels in brain cells (including neurons, astrocytes, and microglia) are extremely low under steady‐state conditions but rise dramatically under pathological inflammatory conditions (Urrutia et al, ; Simpson et al, )‐ suggesting that hepcidin is a causal factor in brain iron retention in the context of neuroinflammation.…”

Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology

“…According to Kulaksiz et al, renal hepcidin is mostly located in the epithelial cells of the cortical thick ascending limb of nephron tubules and in the connecting tubules [34]. Local renal hepcidin produced by these cells is most likely secreted in the luminal surface of the epithelium [21,34,35], though other authors suggest that the local hepcidin could be secreted in bloodstream via basal membrane [36]. Veuthey et al have suggested that prohepcidin is produced by proximal tubule, though it has to be mentioned that authors of this study did not measure mRNA expression, but rather immunohistochemical expression of this peptide, which could mean that the presence of the peptide inside proximal tubular cells is due to absorption from the blood filtrate which contains the systemic form of the peptide [36].…”

“…Finally, studies show that hepcidin might affect renal iron metabolism independently from FPN [21,37,42]. On the other hand, similarly to liver hepcidin, renal hepcidin could be induced through BMP6/SMAD pathway [35]. It is interesting to notice that the knockout of renal BMP6 is related to progressive renal damage due to a significant increase of iron load and oxidative stress [46].…”