Iron Overload Impairs Renal Function and is Associated with Vascular Calcification in Rat Aorta

Overview

Journal Biometals

Specialty Biochemistry

Date 2022 Sep 30

PMID 36178540

Authors

Yanqiu Song

Ning Yang

Hailong Si

Ting Liu

Hongyu Wang

Hua Geng

Qin Qin

Zhigang Guo

Affiliations

Soon will be listed here.

Abstract

Vascular calcification (VC) has been associated with a risk of cardiovascular diseases. Iron may play a critical role in progressive VC. Therefore, we investigated the effects of iron overload on the aorta of rats. A rat model of iron overload was established by intraperitoneal injection of Iron-Dextran. The levels of iron, calcium, and ALP activity were detected. Von Kossa staining and Perl's staining were conducted. The expression of iron metabolism-related and calcification related factors were examined in the aortic tissue of rats. The results showed serum and aortic tissue iron were increased induced by iron overload and excessive iron induced hepatic and renal damage. In iron overload rats, the expression of divalent metal transporter 1 (DMT1) and hepcidin were higher, but ferroportin1 (FPN1) was lower. Von Kossa staining demonstrated calcium deposition in the aorta of iron overload rats. The calcium content and ALP activity in serum and aortic tissue were increased and iron level in aortic tissue highly correlated with calcium content and ALP activity. The expressions of the osteogenic markers were increased while a decrease of Alpha-smooth muscle actin (α-SMA) in the aortic tissue of iron overload rats. IL-24 was increased during the calcification process induced by iron. Overall, we demonstrated excessive iron accumulation in the aortic tissue and induced organs damage. The iron metabolism-related factors were significantly changed during iron overload. Moreover, we found that iron overload leads to calcium deposition in aorta, playing a key role in the pathological process of VC by mediating osteoblast differentiation factors.

Citing Articles

Intravenous iron treatment fuels chronic kidney disease-induced arterial media calcification in rats.

Van den Branden A, Opdebeeck B, Adriaensen S, Evenepoel P, Vanden Berghe T, Verhulst A J Pathol. 2024; 265(2):172-183.

PMID: 39610372 PMC: 11717497. DOI: 10.1002/path.6375.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Odeh D, Orsolic N, Adrovic E, Bilandzic N, Sedak M, Zarkovic I Int J Mol Sci. 2024; 25(12).

PMID: 38928030 PMC: 11203443. DOI: 10.3390/ijms25126323.

Regulated vascular smooth muscle cell death in vascular diseases.

Yin Z, Zhang J, Shen Z, Qin J, Wan J, Wang M Cell Prolif. 2024; 57(11):e13688.

PMID: 38873710 PMC: 11533065. DOI: 10.1111/cpr.13688.

The Role of Trace Elements in Cardiovascular Diseases.

Wechselberger C, Messner B, Bernhard D Toxics. 2023; 11(12).

PMID: 38133357 PMC: 10747024. DOI: 10.3390/toxics11120956.

Effect of iron administration on the aortic iron content and vascular calcification in phosphorus-loaded chronic kidney disease rats.

Nakanishi M, Goto A, Iwasaki T, Nakanishi T, Kuma A, Nanami M BMC Nephrol. 2023; 24(1):373.

PMID: 38102596 PMC: 10725022. DOI: 10.1186/s12882-023-03426-5.

References

Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt S, Moynihan J . Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000; 403(6771):776-81. DOI: 10.1038/35001596. View

Lee S, Lee I, Jeon J . Vascular Calcification-New Insights Into Its Mechanism. Int J Mol Sci. 2020; 21(8). PMC: 7216228. DOI: 10.3390/ijms21082685. View

Liou S, Nguyen T, Hsu J, Sulistyowati E, Huang S, Wu B . The Preventive Effects of Xanthohumol on Vascular Calcification Induced by Vitamin D Plus Nicotine. Antioxidants (Basel). 2020; 9(10). PMC: 7599490. DOI: 10.3390/antiox9100956. View

Shander A, Berth U, Betta J, Javidroozi M . Iron overload and toxicity: implications for anesthesiologists. J Clin Anesth. 2012; 24(5):419-25. DOI: 10.1016/j.jclinane.2011.12.005. View

Matsushima S, Torii M, Ozaki K, Narama I . Iron lactate-induced osteomalacia in association with osteoblast dynamics. Toxicol Pathol. 2003; 31(6):646-54. DOI: 10.1080/01926230390241990. View

Ghio A, Soukup J, Ghio C, Gordon C, Richards J, Schladweiler M . Iron and zinc homeostases in female rats with physically active and sedentary lifestyles. Biometals. 2020; 34(1):97-105. PMC: 8299713. DOI: 10.1007/s10534-020-00266-w. View

Balogh E, Tolnai E, Nagy Jr B, Nagy B, Balla G, Balla J . Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin. Biochim Biophys Acta. 2016; 1862(9):1640-9. DOI: 10.1016/j.bbadis.2016.06.003. View

Shao J, Cheng S, Pingsterhaus J, Charlton-Kachigian N, Loewy A, Towler D . Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005; 115(5):1210-20. PMC: 1077175. DOI: 10.1172/JCI24140. View

Prentice A . Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism. Ann Nutr Metab. 2017; 71 Suppl 3:40-48. DOI: 10.1159/000480743. View

10.

Leopold J . Vascular calcification: Mechanisms of vascular smooth muscle cell calcification. Trends Cardiovasc Med. 2014; 25(4):267-74. PMC: 4414672. DOI: 10.1016/j.tcm.2014.10.021. View

11.

Sun Y, Byon C, Yuan K, Chen J, Mao X, Heath J . Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res. 2012; 111(5):543-52. PMC: 3678289. DOI: 10.1161/CIRCRESAHA.112.267237. View

12.

Ciceri P, Falleni M, Tosi D, Martinelli C, Cannizzo S, Marchetti G . Therapeutic Effect of Iron Citrate in Blocking Calcium Deposition in High Pi-Calcified VSMC: Role of Autophagy and Apoptosis. Int J Mol Sci. 2019; 20(23). PMC: 6928632. DOI: 10.3390/ijms20235925. View

13.

Lin M, Chen T, Leaf E, Speer M, Giachelli C . Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice. Am J Pathol. 2015; 185(7):1958-69. PMC: 4484217. DOI: 10.1016/j.ajpath.2015.03.020. View

14.

Rice A, Mendez M, Hokanson C, Rees D, Bjorkman P . Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter. J Mol Biol. 2009; 386(3):717-32. PMC: 2677177. DOI: 10.1016/j.jmb.2008.12.063. View

15.

Lomashvili K, Cobbs S, Hennigar R, Hardcastle K, ONeill W . Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol. 2004; 15(6):1392-401. DOI: 10.1097/01.asn.0000128955.83129.9c. View

16.

Shao J, Aly Z, Lai C, Cheng S, Cai J, Huang E . Vascular Bmp Msx2 Wnt signaling and oxidative stress in arterial calcification. Ann N Y Acad Sci. 2007; 1117:40-50. DOI: 10.1196/annals.1402.075. View

17.

Mims M, Prchal J . Divalent metal transporter 1. Hematology. 2005; 10(4):339-45. DOI: 10.1080/10245330500093419. View

18.

Talvio K, Kanninen K, White A, Koistinaho J, Castren M . Increased iron content in the heart of the Fmr1 knockout mouse. Biometals. 2021; 34(4):947-954. PMC: 8313461. DOI: 10.1007/s10534-021-00320-1. View

19.

Hunter L, Shiekh F, Pisimisis G, Kim S, Edeh S, Miller V . Key role of alkaline phosphatase in the development of human-derived nanoparticles in vitro. Acta Biomater. 2010; 7(3):1339-45. PMC: 3031733. DOI: 10.1016/j.actbio.2010.10.027. View

20.

Dev S, Babitt J . Overview of iron metabolism in health and disease. Hemodial Int. 2017; 21 Suppl 1:S6-S20. PMC: 5977983. DOI: 10.1111/hdi.12542. View