Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload

Chaudhary, Kapil; Chilakala, Aruna; Ananth, Sudha; Mandala, Ashok; Veeranan-Karmegam, Rajalakshmi; Powell, Folami Lamoke; Ganapathy, Vadivel; Gnana-Prakasam, Jaya P.

doi:10.1152/ajprenal.00184.2019

Cited by 30 publications

(29 citation statements)

References 25 publications

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“…Ferroptosis is a form of regulated cell death that is induced by iron overloading ( 1 ). Renal iron accumulation has been proposed to promote the progression of DN ( 33 , 34 ). However, Ferrostatin-1 can form a complex compounded with iron ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…Degradation of heme by the excessive HO-1 leads to iron overloading which causes oxidative stress and lipid peroxidation. Recent studies have documented the great effects of iron accumulation in kidneys on the progression of DN ( 33 , 34 ). These studies suggested that the process of ferroptosis might affect the development of DN, diabetic renal tubular injury in particular, through HIF-1α/HO-1 pathway.…”

Section: Introductionmentioning

confidence: 99%

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Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

et al. 2021

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BackgroundFerroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice.MethodsDb/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice.ResultsDb/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice.ConclusionsOur study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

et al. 2021

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“…In a diabetic circumstance, cytokines cause an increase in transferrin receptors on the cell surface, favoring tissue accumulation of transferrin and deposition of iron 32 . Iron nephrotoxicity is due to 1) the production of cell-damaging reactive radicals by Fenton reactions, and 2) ferroptosis, programmed cell death triggered by iron 33 , and 3) iron-induced RAS activation by upregulation of intra renal renin expression 34 .…”

Section: Discussionmentioning

confidence: 99%

Serum transferrin predicts end-stage Renal Disease in Type 2 Diabetes Mellitus patients

Zhao¹,

Zou²,

Zhang³

et al. 2020

Int. J. Med. Sci.

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Background: To investigate the relationship between serum iron status and renal outcome in patients with type 2 diabetes mellitus (T2DM). Methods: Chinese patients (n=111) with T2DM and biopsy-proven diabetic nephropathy (DN) were surveyed in a longitudinal, retrospective study. Serum iron, total iron-binding capacity, ferritin, and transferrin were measured at the time of renal biopsy. Iron deposition and transferrin staining were performed with renal biopsy specimens of DN patients and potential kidney donors. End-stage renal disease (ESRD) was the end-point. ESRD was defined as an estimated glomerular filtration rate <15 mL/min/1.73 m 2 or the need for chronic renal replacement therapy. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for the influence of serum iron metabolism on ESRD. Results: During a median follow up of 30.9 months, 66 (59.5%) patients progressed to ESRD. After adjusting for age, sex, baseline systolic blood pressure, renal functions, hemoglobin, HbA1c, and pathological findings, lower serum transferrin concentrations were significantly associated with higher ESRD in multivariate models. Compared with patients in the highest transferrin quartile (≥1.65 g/L), patients in the lowest quartile (≤1.15 g/L) had multivariable-adjusted HR (95% confidence interval) of 7.36 (1.40-38.65) for ESRD. Moreover, tubular epithelial cells in DN exhibited a higher deposition of iron and transferrin expression compared with healthy controls. Conclusions: Low serum transferrin concentration was associated with diabetic ESRD in patients with T2DM. Free iron nephrotoxicity and poor nutritional status with accumulated iron or transferrin deposition might contribute to ESRD.

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“…Through these mechanisms, iron overload aggravated the progression of DR in mice. Chaudhary et al 33 reported that renal iron accelerated the progression of diabetic nephropathy in association with renal–renin–angiotensin system activation. These results remain to be confirmed in future clinical research.…”

Section: Discussionmentioning

confidence: 99%

The Relationship of Hyperferritinemia to Metabolism and Chronic Complications in Type 2 Diabetes

Shang¹,

Zhang²,

Wang³

et al. 2022

DMSO

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Aim Elevated serum ferritin has been found to be closely related to type 2 diabetes mellitus. This study aimed to explore the relationship of high serum ferritin to metabolism and chronic complications in type 2 diabetes. Methods This was a cross-sectional study. A total of 330 type 2 diabetes patients who visited an endocrine clinic were included for the analysis. Serum ferritin and metabolic parameters were recorded. The prevalence of chronic diabetic complications was evaluated. Based on serum ferritin, participants were divided into hyperferritinemia and normal-ferritin groups. Metabolic parameters and prevalence of chronic diabetic complications were compared. The relationship between hyperferritinemia and chronic diabetic complications was explored with multivariate logistic regression models. Data were statistically analyzed by sex. Results Compared with the normal-ferritin group, the hyperferritinemia group showed higher levels of the serum inflammatory marker CRP and higher prevalence of diabetic retinopathy (DR) and coronary heart disease (CHD), regardless of sex ( p <0.05). Moreover, male patients with hyperferritinemia had increased serum triglyceride, alanine transferase, γ-glutamyltranspeptidase, urea nitrogen, creatinine, and uric acid and higher prevalence of microalbuminuria ( p <0.01). After controlling for demographics and metabolic profiles, hyperferritinemia remained an independent risk factor of DR (male OR 3.957, 95% CI 1.559–10.041, p =0.004; female OR 2.474, 95% CI 1.127–5.430, p =0.024) and CHD (male OR 2.607, 95% CI 1.087–6.257, p =0.032; female OR 2.293, 95% CI 1.031–5.096, p =0.042). Conclusion This study found that hyperferritinemia was associated with increased CRP and higher prevalence of DR and CHD in type 2 diabetes. In men, high serum ferritin was also associated with dyslipidemia, hepatic dysfunction, and microalbuminuria.

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Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload

Cited by 30 publications

References 25 publications

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice

Serum transferrin predicts end-stage Renal Disease in Type 2 Diabetes Mellitus patients

The Relationship of Hyperferritinemia to Metabolism and Chronic Complications in Type 2 Diabetes

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