Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jun 19;8(1):9353.
doi: 10.1038/s41598-018-27107-8.

Tubular Iron Deposition and Iron Handling Proteins in Human Healthy Kidney and Chronic Kidney Disease

Affiliations
Free PMC article

Tubular Iron Deposition and Iron Handling Proteins in Human Healthy Kidney and Chronic Kidney Disease

Sanne van Raaij et al. Sci Rep. .
Free PMC article

Erratum in

Abstract

Iron is suggested to play a detrimental role in the progression of chronic kidney disease (CKD). The kidney recycles iron back into the circulation. However, the localization of proteins relevant for physiological tubular iron handling and their potential role in CKD remain unclear. We examined associations between iron deposition, expression of iron handling proteins and tubular injury in kidney biopsies from CKD patients and healthy controls using immunohistochemistry. Iron was deposited in proximal (PT) and distal tubules (DT) in 33% of CKD biopsies, predominantly in pathologies with glomerular dysfunction, but absent in controls. In healthy kidney, PT contained proteins required for iron recycling including putative iron importers ZIP8, ZIP14, DMT1, iron storage proteins L- and H-ferritin and iron exporter ferroportin, while DT only contained ZIP8, ZIP14, and DMT1. In CKD, iron deposition associated with increased intensity of iron importers (ZIP14, ZIP8), storage proteins (L-, H-ferritin), and/or decreased ferroportin abundance. This demonstrates that tubular iron accumulation may result from increased iron uptake and/or inadequate iron export. Iron deposition associated with oxidative injury as indicated by heme oxygenase-1 abundance. In conclusion, iron deposition is relatively common in CKD, and may result from altered molecular iron handling and may contribute to renal injury.

Conflict of interest statement

RvS and DS are managing director and medical director, respectively, of ‘Hepcidinanalysis.com’, which aims to serve the community with high–quality hepcidin measurements, but do not have non-financial interests. All other authors declare no competing interests.

Figures

Figure 1
Figure 1
Iron deposition in chronic kidney disease. Representative images of Perls’ staining in healthy control (a), diabetic nephropathy (b), membranous glomerulopathy (MG; c), IgA nephropathy (d), focal segmental glomerulosclerosis (FSGS; e), minimal change disease (f), lupus nephritis (g), Wegener’s disease (h), hypertension nephropathy (i), anti-glomerular basement membrane (GBM) disease (j), and thin basement membrane disease (TBMD; k). Renal structures indicated as glomerulus (G), proximal tubule (PT), distal tubule (DT). Iron indicated with arrows. Scale bar 20 µM.
Figure 2
Figure 2
Immunohistochemistry of iron handling proteins in healthy kidney. Representatives images of ZIP8 (a), ZIP14 (b), divalent metal transporter 1 (DMT1; c), L-ferritin (d), H-ferritin (e), and ferroportin (f) staining in healthy kidney. Renal structures indicated as glomerulus (g), proximal tubule (PT), distal tubule (DT). Scale bar 20 µM.
Figure 3
Figure 3
Immunohistochemistry of putative iron importers in chronic kidney disease. Representative images of ZIP8 (af), ZIP14 (gl), and divalent metal transporter 1 (DMT1; mr) staining in control (a,g,m), early diabetic nephropathy (DNE; b,h,n), advanced diabetic nephropathy (DNA; c,i,o), focal segmental glomerulosclerosis (FSGS; d,j,p), lupus nephritis (LN; e,k,q) and IgA nephropathy (IgAN; f,l,r). Intensity in proximal and distal tubules quantified (s). Dots represent all quantified images (5 images per biopsy). Renal structures indicated as glomerulus (G), proximal tubule (PT), distal tubule (DT). Scale bar 40 µM. **p < 0.01; ***p < 0.001.
Figure 4
Figure 4
Immunohistochemistry of intracellular iron handling proteins in chronic kidney disease. Representative images of L-ferritin (af) and H-ferritin (gl) staining in control (a,g), early diabetic nephropathy (DNE; b,h), advanced diabetic nephropathy (DNA; c,i), focal segmental glomerulosclerosis (FSGS; d,j), lupus nephritis (LN; e,k), and IgA nephropathy (IgAN; f,l). Intensity quantified (m) in proximal tubules. Dots represent all quantified images (5 images per biopsy). Renal structures indicated as glomerulus (G), proximal tubule (PT), distal tubule (DT). Scale bar 40 µM. *p < 0.05; ***p < 0.001.
Figure 5
Figure 5
Immunohistochemistry of cellular iron export protein in chronic kidney disease. Representative images of ferroportin staining in control (a), early diabetic nephropathy (DNE; b), advanced diabetic nephropathy (DNA; c), focal segmental glomerulosclerosis (FSGS; d), lupus nephritis (LN; e), and IgA nephropathy (IgAN; f). Intensity quantified (g) in proximal tubules. Dots represent all quantified images (5 images per biopsy). Renal structures indicated as glomerulus (G), proximal tubule (PT), distal tubule (DT). Scale bar 40 µM. **p < 0.01; ***p < 0.001.
Figure 6
Figure 6
Overview of observations on iron deposition and intensity of iron handling proteins in chronic kidney disease. Overview of iron deposition (in blue) and iron handling protein intensity in healthy control (a), early diabetic nephropathy (DNE; b), advanced diabetic nephropathy (DNA; c), focal segmental glomerulosclerosis (FSGS; d), lupus nephritis (LN; e), and IgA nephropathy (IgAN; f ). Increased protein intensity compared to healthy controls (in grey) visualized in green, decreased protein intensity in red. DMT1, divalent metal transporter 1.
Figure 7
Figure 7
PAS staining for tubular injury in chronic kidney disease. Representative images of PAS staining in control (a) or chronic kidney disease showing atrophic tubules with loss of brush border and enlarged basement membrane (b), blebbed tubules (c) and interstitial fibrosis (d). Percentage of tissue with tubular injury scored (E) per patient. Renal structures indicated as glomerulus (G), proximal tubule (PT), and distal tubule (DT). Symbols indicate proximal tubular brush border with asterisk, blebbed tubules with double asterisk, basement membrane with arrow, and fibrosis with hashtag. Scale bar 20 µM.
Figure 8
Figure 8
Immunohistochemistry of injury marker HO-1 in chronic kidney disease. Representative images of heme oxygenase-1 (HO-1) staining in control (a), early diabetic nephropathy (DNE; b), advanced diabetic nephropathy (DNA; c), focal segmental glomerulosclerosis (FSGS; d), lupus nephritis (LN; e), and IgA nephropathy (IgAN; f). Renal structures indicated as glomerulus (G), proximal tubule (PT), and distal tubule (DT). Scale bar 40 µM.

Similar articles

See all similar articles

Cited by 5 articles

References

    1. Coresh J. Update on the Burden of CKD. J Am Soc Nephrol. 2017;28:1020–1022. doi: 10.1681/ASN.2016121374. - DOI - PMC - PubMed
    1. Ruggenenti P, Cravedi P, Remuzzi G. Mechanisms and treatment of CKD. Journal of the American Society of Nephrology: JASN. 2012;23:1917–1928. doi: 10.1681/ASN.2012040390. - DOI - PubMed
    1. Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. British journal of clinical pharmacology. 2013;76:516–523. - PMC - PubMed
    1. de Borst MH, et al. Active vitamin D treatment for reduction of residual proteinuria: a systematic review. Journal of the American Society of Nephrology: JASN. 2013;24:1863–1871. doi: 10.1681/ASN.2013030203. - DOI - PMC - PubMed
    1. Martines AM, et al. Iron metabolism in the pathogenesis of iron-induced kidney injury. Nature reviews. Nephrology. 2013;9:385–398. doi: 10.1038/nrneph.2013.98. - DOI - PubMed

Publication types

Feedback