Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease

Raaij, S.E.G. van; Swelm, Rachel van; Bouman, Karlijn; Cliteur, Maaike; Heuvel, Marius C. van den; Pertijs, Jeanne; Patel, Dominic; Bass, Paul; Goor, Harry van; Unwin, Robert J.; Srai, Surjit Kaila; Swinkels, Dorine W.

doi:10.1038/s41598-018-27107-8

Cited by 89 publications

(91 citation statements)

References 62 publications

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“…In human hepatocytes, DMT1 was detected at the plasma membrane and was found to mediate NTBI uptake in these cells (Shindo et al 2006 ). Although we previously detected DMT1 in human PTs (van Raaij et al 2018 ), it was not present at the plasma membrane in ciPTECs. As a result, we believed that a role for DMT1 in direct NTBI uptake at the plasma membrane was unlikely and focussed our studies on ZIP8 and ZIP14.…”

Section: Discussionmentioning

confidence: 57%

“…As such, mutations in ZIP8 and ZIP14 in patients both lead to changes in metal transport, but show distinct phenotypes (Boycott et al 2015 ; Li et al 2016 ; Park et al 2015 ; Tuschl et al 2016 ). In addition to PTs, ZIP8 and ZIP14 are also present in human distal tubular epithelial cells (Ajjimaporn et al 2012 ; van Raaij et al 2018 ), but it remains to be investigated to what extent both transporters are involved in NTBI handling in the distal nephron.…”

Section: Discussionmentioning

confidence: 99%

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Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells

et al. 2019

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In patients with iron overload disorders, increasing number of reports of renal dysfunction and renal iron deposition support an association between increased iron exposure and renal injury. In systemic iron overload, elevated circulating levels of transferrin-bound (TBI) and non-transferrin-bound iron (NTBI) are filtered to the renal proximal tubules, where they may cause injury. However, the mechanisms of tubular iron handling remain elusive. To unravel molecular renal proximal tubular NTBI and TBI handling, human conditionally immortalized proximal tubular epithelial cells (ciPTECs) were incubated with 55 Fe as NTBI and fluorescently labeled holo-transferrin as TBI. Ferrous iron importers ZIP8 and ZIP14 were localized in the ciPTEC plasma membrane. Whereas silencing of either ZIP8 or ZIP14 alone did not affect 55 Fe uptake, combined silencing significantly reduced 55 Fe uptake compared to control (p < 0.05). Furthermore, transferrin receptor 1 (TfR1) and ZIP14, but not ZIP8, colocalized with early endosome antigen 1 (EEA1). TfR1 and ZIP14 also colocalized with uptake of fluorescently labeled transferrin. Furthermore, ZIP14 silencing decreased 55 Fe uptake after 55 Fe-Transferrin exposure (p < 0.05), suggesting ZIP14 could be involved in early endosomal transport of TBI-derived iron into the cytosol. Our data suggest that human proximal tubular epithelial cells take up TBI and NTBI, where ZIP8 and ZIP14 are both involved in NTBI uptake, but ZIP14, not ZIP8, mediates TBI-derived iron uptake. This knowledge provides more insights in the mechanisms of renal iron handling and suggests that ZIP8 and ZIP14 could be potential targets for limiting renal iron reabsorption and enhancing urinary iron excretion in systemic iron overload disorders. Electronic supplementary material The online version of this article (10.1007/s10534-019-00183-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells

et al. 2019

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“…Alternatively, urinary iron excretion can result from insufficient iron reabsorption in either PTs or DTs. Filtered proteins, including TBI (23,24), are predominantly reabsorbed by PTs (25), but also DTs express transporters involved in iron handling and are reported to take up TBI (26,27). Increased urinary transferrin levels in patients with Fanconi syndrome, characterized by compromised proximal tubular reabsorption (1), suggest the tubular reabsorption capacity affects urinary transferrin levels, and similarly, possibly also urinary iron levels.…”

Section: Introductionmentioning

confidence: 99%

Iron handling by the human kidney: glomerular filtration and tubular reabsorption both contribute to urinary iron excretion

Raaij

Rennings

Biemond

et al. 2019

American Journal of Physiology-Renal Physiology

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In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects ( n = 20), patients with systemic iron overload ( n = 20), and patients with renal tubular dysfunction ( n = 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury.

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“…Iron is not normally stored in the kidneys in great quantities and is only minimally excreted in urine since most circulating iron is bound to proteins such as the iron-transport protein, transferrin, and iron that does pass into the renal tubules is mostly reabsorbed 55 . Increased levels of iron have been found in the kidney tissue, associated with glomerular lesions 56,57 , and urine 53,58 of human CKD patients compared to humans without renal disease. However, we measured lower concentrations of iron in cat, compared to dog, kidneys and, in both species, in kidneys with CIN compared to those without.…”

Section: Renal Histopathology and Prevalence Of Chronic Interstitial mentioning

confidence: 99%

Renal accumulation of prooxidant mineral elements and CKD in domestic cats

Alborough

Grau‐Roma

Brot

et al. 2020

Sci Rep

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felids have a high incidence of chronic kidney disease (cKD), for which the most common renal lesion is chronic interstitial nephritis (cin). cin can be induced by tissue oxidative stress, which is determined by the cellular balance of pro-and anti-oxidant metabolites. Fish-flavoured foods are more often fed to cats than dogs, and such foods tend to have higher arsenic content. Arsenic is a pro-oxidant metallic element. We propose that renal accumulation of pro-oxidant elements such as arsenic and depletion of anti-oxidant elements such as zinc, underpin the high incidence of cin in domestic cats. total arsenic and other redox-reactive metal elements were measured in kidneys (after acid-digestion) and urine (both by inductively-coupled plasma-mass spectrometry) of domestic cats (kidneys, n = 56; urine, n = 21), domestic dogs (kidneys, n = 54; urine, n = 28) and non-domesticated Scottish Wildcats (kidneys, n = 17). Renal lesions were graded by severity of CIN. In our randomly sampled population, CIN was more prevalent in domestic cat versus domestic dog (51%, n = 32 of 62 cats; 15%, 11 of 70 dogs were positive for cin, respectively). cin was absent from all Scottish wildcats. tissue and urinary (corrected for creatinine) arsenic content was higher in domestic cats, relative to domestic dogs and wildcats. Urine arsenic was higher in domestic cats and dogs with cin. Arsenobetaine, an organic and relatively harmless species of arsenic, was the primary form of arsenic found in pet foods. in summary, the kidneys of domestic cats appear to have greater levels of pro-oxidant trace elements, as compared to dogs and wildcats. Since there was no difference in renal arsenic levels in cats with or without CIN, renal arsenic accumulation does not appear a primary driver of excess CIN in cats. Given clear differences in renal handling of pro vs. anti-oxidant minerals between cats and dogs, further in vivo balance studies are warranted. These may then inform species-specific guidelines for trace element incorporation into commercial diets.Chronic kidney disease (CKD) is commonly diagnosed in domestic cats, with a reported prevalence of 1-3% in the overall domestic cat population 1 . One study reported prevalence as high as 50% and 80% in cats of all ages and aged over 15 years, respectively 2 . This contrasts to a reported prevalence of <1% in all dogs 3 and only 10% in dogs over 15 years of age 1 . CKD is defined as the irreversible loss of structure and/or function of one or both kidneys that results from a progressive process occurring over a period of 3 months or more 1 . CKD has various aetiologies, but mononuclear cell tubulointerstitial nephritis -inflammation of the interstitial cells surrounding tubules, predominantly proximal -together with interstitial fibrosis and tubular atrophy is the common histopathological finding in most cases of CKD in cats 4,5 and dogs 6 .Renal tubular epithelial cells are highly metabolically active with high mitochondrial density in order to support oxidative phosphorylation and energy-depe...

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Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease

Cited by 89 publications

References 62 publications

Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells

Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells

Iron handling by the human kidney: glomerular filtration and tubular reabsorption both contribute to urinary iron excretion

Renal accumulation of prooxidant mineral elements and CKD in domestic cats

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