Hepcidin regulates intrarenal iron handling at the distal nephron

Abstract

Hepcidin, the key regulatory hormone of iron homeostasis, and iron carriers such as transferrin receptor1 (TFR1), divalent metal transporter1 (DMT1), and ferroportin (FPN) are expressed in kidney. Whether hepcidin plays an intrinsic role in the regulation of renal iron transport is unknown. Here, we analyzed the renal handling of iron in hemochromatosis Hepc(-/-) and Hjv(-/-) mouse models, as well as in phenylhydrazine (PHZ)-treated mice. We found a marked medullary iron deposition in the kidneys of Hepc(-/-) mice, and iron leak in the urine. The kidneys of Hepc(-/-) mice exhibited a concomitant decrease in TFR1 and increase in ferritin and FPN expression. Increased FPN abundance was restricted to the thick ascending limb (TAL). DMT1 protein remained unaffected despite a significant decrease of its mRNA level, suggesting that DMT1 protein is stabilized in the absence of hepcidin. Treatment of kidney sections from Hepc(-/-) mice with hepcidin decreased DMT1 protein, an effect confirmed in renal cell lines where hepcidin markedly decreased (55)Fe transport. In the kidneys of Hjv(-/-) mice exhibiting low hepcidin expression, the iron overload was similar to that in the kidneys of Hepc(-/-) mice. However, in PHZ mice, iron accumulation resulting from hemoglobin leak was detected in the proximal tubule. Thus, kidneys exhibit a tissue-specific handling of iron that depends on the extra iron source. Hepcidin may control the expression of iron transporters to prevent renal iron overload.

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

“…Furthermore, Perl's staining in CEP mice shows that heavy iron deposits in the liver were restricted to Kupffer cells while only a diffuse, fainter staining was observed in hepatocytes ( Figure 4A). This pattern of iron accumulation differs from the primary hemochromatosis mouse models (including Hjv -/-mice) [26][27][28] where Tf saturation is high 19 and iron is mostly accumulated in hepatocytes ( Figure 4A). Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv -/-mice ( Figure 4B), confirming that Hb and "free" heme are the likely source of macrophage iron accumulation.…”

“…We have previously shown that the kidney exhibits a cell specificity of iron handling in the kidney, which depends on the pathological origin of the iron overload. In hemochromatosis models, transferrin-bound iron was specifically handled in the thick ascending limb; 19 however, as shown in our hemolytic model, Hb-bound iron was specifically taken up by the proximal tubule, the endocytic megalin/cubilin complex was stimulated, and HO-1 and ferroportin were induced to generate and return iron to the bloodstream, although the urinary iron-bound Hb losses remained significant and certainly contribute to the hypochromic anemia. The involvement of renal megalin/cubilin receptors for the binding and uptake of Hb has been previously demonstrated by in vitro studies and mouse models.…”

“…18,19 Briefly, 10-20 µg of crude membrane proteins were solubilized in 1× Laemmli buffer, analyzed by SDS/PAGE and transferred onto a PVDF membrane for HO-1, ferroportin, TfR1, H-ferritin and DMT1. For Hpx detection, 1 μL of plasma was loaded on SDS/PAGE and transferred onto nitrocellulose membrane.…”

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

“…7 Hepcidin has been discovered in 2000 as an antimicrobial peptide 8,9 and in 2001 as a hyposideremic peptide. 10,11 Hepcidin is mainly produced by hepatocytes in response to increased serum and tissue iron, 10,11 and inhibits iron efflux from duodenal enterocyte and macrophage stores.…”

“…25 Notably, hepcidin expression was recently identified in several epithelial barriers that are frequently confronted by pathogen infection, including renal distal nephron. 7,[26][27][28] However, whether hepcidin is required for resistance to epithelial barrier infection has received little attention. Here, we provide evidence that hepcidin may represent an effective defense system against UPEC infection and more interestingly that UPEC represses local hepcidin to evade renal host defenses during UTI.…”