Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria

Abstract

Proteins involved in iron homeostasis have been identified as biomarkers for lupus nephritis, a serious complication of systemic lupus erythematosus (SLE). We tested the hypothesis that renal iron accumulation occurs and contributes to renal injury in SLE. Renal non-heme iron levels were increased in the (New Zealand Black x New Zealand White) F1 (NZB/W) mouse model of lupus nephritis compared with healthy New Zealand White (NZW) mice in an age- and strain-dependent manner. Biodistribution studies revealed increased transferrin-bound iron accumulation in the kidneys of albuminuric NZB/W mice, but no difference in the accumulation of non-transferrin bound iron or ferritin. Transferrin excretion was significantly increased in albuminuric NZB/W mice, indicating enhanced tubular exposure and potential for enhanced tubular uptake following filtration. Expression of transferrin receptor and 24p3R were reduced in tubules from NZB/W compared to NZW mice, while ferroportin expression was unchanged and ferritin expression increased, consistent with increased iron accumulation and compensatory downregulation of uptake pathways. Treatment of NZB/W mice with the iron chelator deferiprone significantly delayed the onset of albuminuria and reduced blood urea nitrogen concentrations. Together, these findings suggest that pathological changes in renal iron homeostasis occurs in lupus nephritis, contributing to the development of kidney injury.

Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis

“…Iron accumulation has been observed in nephritic kidneys. 22 As hepcidin affects systemic iron stores, we evaluated renal and splenic iron accumulation and its relation to the outcome of LN. Compared with PBS-treated mice, the kidneys of hepcidin-treated mice contained less Perl's stainable iron in tubules and interstitial regions (Supplementary Figure S1A).…”

“…mice 22 and deferiprone, a U.S. Food and Drug Administration-approved iron chelator, delayed the onset of albuminuria, thereby highlighting iron metabolism as a potential therapeutic target.…”

<p>BCc1 Nanomedicine Therapeutic Effects in Streptozotocin and High-Fat Diet Induced Diabetic Kidney Disease</p>

“…53 Also Marks et al, reported that the mentioned iron chelator could delay the onset of albuminuria and reduced BUN concentrations. 15 It should be noted that due to the role of iron in different vital processes, especially hematopoiesis, any interventions by chelation therapy must have no negative effects on iron-related physiological parameters, and due to the importance of this, in the present study, hepatic iron content and RBC count, Hb, Hct and MCV levels were assayed, the results of which showed no negative effects of using BCc1 on important iron-related physiological parameters. On the other hand, this nanomedicine significantly decreased urine MDA and 8-isoprostane concentration as the well-known markers of oxidative stress, 54,55 and previous studies have already proved that the production of these markers is closely related to iron metabolism disruption.…”

“…46 To break the harmful cycle, several studies have evaluated the effects of iron chelators in these situations. [14][15][16][17] In the previous studies, anti-neoplastic effects of BCc1 nanomedicine with iron-chelating property were demonstrated in several experiments. 19,20,47 In the present study, this nanomedicine was tested in animal model of DKD to evaluate its impacts on various biochemical and histopathological parameters of this disease.…”

“…[5][6][7] Although iron as a trace element has vital roles in the physiology of human beings, it is a redox-active element, so a vicious cycle of iron dis-homeostasis, inflammation and oxidative stress is formed mostly through free radicals induced by iron in chronic diseases, [8][9][10][11][12] and therefore manipulation of iron homeostasis in chronic diseases, especially in DKD, is evaluated in dozens of studies using iron chelators to assess their impacts. [13][14][15][16][17] In fact, iron chelation in these situations means iron re-distribution, not iron excretion. 18 In the previous studies, anti-neoplastic effects of BCc1 nanostructure, synthetized based on nanochelating technology, were evaluated in animal models of breast cancer, proving increase in survival and reduction in tumor size growth.…”