Endothelin A receptor antagonist attenuated renal iron accumulation in iron overload heme oxygenase-1 knockout mice
Publication: Canadian Journal of Physiology and Pharmacology
12 April 2022
Abstract
Progressive iron accumulation and renal impairment are prominent in both patients and mouse models of sickle cell disease (SCD). Endothelin A receptor (ETA) antagonism prevents this iron accumulation phenotype and reduces renal iron deposition in the proximal tubules of SCD mice. To better understand the mechanisms of iron metabolism in the kidney and the role of the ETA receptor in iron chelation and transport, we studied renal iron handling in a nonsickle cell iron overload model, heme oxygenase-1 (Hmox-1−/−) knockout mice. We found that Hmox-1−/− mice had elevated plasma endothelin-1 (ET-1), cortical ET-1 mRNA expression, and renal iron content compared with Hmox-1+/+ controls. The ETA receptor antagonist, ambrisentan, attenuated renal iron deposition, without any changes to anemia status in Hmox-1−/− mice. This was accompanied by reduced urinary iron excretion. Finally, ambrisentan had an important iron recycling effect by increasing the expression of the cellular iron exporter, ferroportin-1 (FPN-1), and circulating total iron levels in Hmox-1−/− mice. These findings suggest that the ET-1/ETA signaling pathway contributes to renal iron trafficking in a murine model of iron overload.
Graphical Abstract
Résumé
L’accumulation progressive de fer et l’insuffisance rénale progressive se retrouvent de manière proéminente chez les patients atteints d’anémie falciforme (AF) comme dans les modèles de la maladie chez la souris. L’antagonisme des récepteurs de l’endothéline A (ETA) permet de prévenir ce phénotype d’accumulation de fer et d’atténuer le dépôt de fer au niveau des tubules proximaux des reins de souris AF. Afin de mieux comprendre les modes d’action du métabolisme du fer dans les reins et le rôle des récepteurs ETA dans la chélation et le transport du fer, nous avons étudié la gestion du fer rénal dans un modèle de surcharge en fer sans AF : la souris « knock-out » hème oxygénase 1 (Hmox-1-/-). Nous avons observé que la souris Hmox-1-/- présentait des taux plasmatiques d’endothéline 1 (ET-1), une expression corticale d’ET-1 en ARNm et des taux de fer dans les reins plus élevés que les témoins Hmox-1+/+. L’ambrisentane, un antagoniste des récepteurs ETA, permettait d’atténuer le dépôt de fer dans les reins sans aucune modification de l’état anémique des souris Hmox-1-/-, ce qui s’accompagnait d’une diminution de l’excrétion urinaire du fer. Enfin, l’ambrisentane avait un important effet de recyclage du fer par l’entraînement d’un accroissement de l’expression de la ferroportine 1 (FPN-1), un exportateur de fer cellulaire, de même que des taux de fer en circulation chez les souris Hmox-1-/-. Ces résultats laissent entendre que la voie de signalisation ET-1/ETA participerait au trafic du fer rénal dans un modèle de surcharge en fer chez la souris.
Get full access to this article
View all available purchase options and get full access to this article.
References
Anderson S.A., Nizzi C.P., Chang Y.I., Deck K.M., Schmidt P.J., Galy B., et al. 2013. The IRP1-HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 17(2): 282–290.
Bakrania B.A., Spradley F.T., Satchell S.C., Stec D.E., Rimoldi J.M., Gadepalli R.S.V., et al. 2018. Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 314(3): R427–R432.
Banyai E., Balogh E., Fagyas M., Arosio P., Hendrik Z. Kiraly G., et al. 2014. Novel functional changes during podocyte differentiation: increase of oxidative resistance and H-ferritin expression. Oxid. Med. Cell. Longev. 2014: 976394.
Batchelor E.K., Kapitsinou P., Pergola P.E., Kovesdy C.P., Jalal D.I. 2020. Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment. J. Am. Soc. Nephrol. 31(3): 456–468.
Bickford J.S., Ali N.F., Nick J.A., Al-Yahia M., Beachy D.E., Dore S., et al. 2014. Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism. Brain Res. 1588: 25–36.
Bolisetty S., Traylor A.M., Kim J., Joseph R., Ricart K., Landar A., et al. 2010. Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury. J. Am. Soc. Nephrol. 21(10): 1702–1712.
Bouri S., Martin J. 2018. Investigation of iron deficiency anaemia. Clin. Med. (Lond). 18(3): 242–244.
Cai L., Chen S., Evans T., Cherian M.G., Chakrabarti S. 2002. Endothelin-1-mediated alteration of metallothionein and trace metals in the liver and kidneys of chronically diabetic rats. Int. J. Exp. Diabetes Res. 3(3): 193–198.
Christensen E.I., Birn H. 2002. Megalin and cubilin: multifunctional endocytic receptors. Nat. Rev. Mol. Cell Biol. 3(4): 256–266.
Dhaun N., Webb D.J., Kluth D.C. 2012. Endothelin-1 and the kidney: beyond BP. Br. J. Pharmacol. 167(4): 720–731.
Drakesmith H., Nemeth E., Ganz T. 2015. Ironing out ferroportin. Cell Metab. 22(5): 777–787.
Ergul S., Brunson C.Y., Hutchinson J., Tawfik A., Kutlar A., Webb R.C., et al. 2004. Vasoactive factors in sickle cell disease: in vitro evidence for endothelin-1-mediated vasoconstriction. Am. J. Hematol. 76(3): 245–251.
Finazzi D., Arosio P. 2014. Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch. Toxicol. 88(10): 1787–1802.
Fox B.M., Kasztan M. 2016. Endothelin receptor antagonists in sickle cell disease: a promising new therapeutic approach. Life Sci. 159: 15–19.
Fung E.B., Harmatz P., Milet M., Ballas S.K., De Castro L., Hagar W., et al. 2007. Morbidity and mortality in chronically transfused subjects with thalassemia and sickle cell disease: a report from the multi-center study of iron overload. Am. J. Hematol. 82(4): 255–265.
Gburek J., Verroust P.J., Willnow T.E., Fyfe J.C., Nowacki W., Jacobsen C., et al. 2002. Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin. J. Am. Soc. Nephrol. 13(2): 423–430.
George E.M., Cockrell K., Aranay M., Csongradi E., Stec D.E., Granger J.P. 2011. Induction of heme oxygenase 1 attenuates placental ischemia-induced hypertension. Hypertension, 57(5): 941–948.
Ghosh M.C., Zhang D.L., Jeong S.Y., Kovtunovych G., Ollivierre-Wilson H., Noguchi A., et al. 2013. Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. Cell Metab. 17(2): 271–281.
Gohar E.Y., Giachini F.R., Pollock D.M., Tostes R.C. 2016. Role of the endothelin system in sexual dimorphism in cardiovascular and renal diseases. Life Sci. 159: 20–29.
Heerspink H.J.L., Parving H.H., Andress D.L., Bakris G., Correa-Rotter R., Hou F.F., et al. 2019. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet, 393(10184): 1937–1947.
Heimlich J.B., Speed J.S., O'Connor P.M., Pollock J.S., Townes T.M., Meiler S.E., et al. 2016. Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br. J. Pharmacol. 173(2): 386–395.
Kapturczak M.H., Wasserfall C., Brusko T., Campbell-Thompson M., Ellis T.M., Atkinson M.A., et al. 2004. Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am. J. Pathol. 165(3): 1045–1053.
Kasztan M., Alrefai H., Taylor C., Pollock D.M. 2020. Proximal tubule albumin uptake: potential role for the endothelin system in sickle cell disease mice. FASEB J. 34(S1): 1.
Kasztan M., Pollock D.M. 2019. Impact of ET-1 and sex in glomerular hyperfiltration in humanized sickle cell mice. Clin. Sci. (Lond). 133(13): 1475–1486.
Kasztan M., Fox B.M., Lebensburger J.D., Hyndman K.A., Speed J.S., Pollock J.S., et al. 2019. Hyperfiltration predicts long-term renal outcomes in humanized sickle cell mice. Blood Adv. 3(9): 1460–1475.
Kasztan M., Fox B.M., Speed J.S., De Miguel C., Gohar E.Y., Townes T.M., et al. 2017. Long-term endothelin-A receptor antagonism provides robust renal protection in humanized sickle cell disease mice. J. Am. Soc. Nephrol. 28(8): 2443–2458.
Kawashima A., Oda Y., Yachie A., Koizumi S., Nakanishi I. 2002. Heme oxygenase-1 deficiency: the first autopsy case. Hum. Pathol. 33(1): 125–130.
Kittikulsuth W., Sullivan J.C., Pollock D.M. 2013. ET-1 actions in the kidney: evidence for sex differences. Br. J. Pharmacol. 168(2): 318–326.
Kohan D.E., Barton M. 2014. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 86(5): 896–904.
Koury M.J., Haase V.H. 2015. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat. Rev. Nephrol. 11(7): 394–410.
Kovtunovych G., Eckhaus M.A., Ghosh M.C., Ollivierre-Wilson H., Rouault T.A. 2010. Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. Blood, 116(26): 6054–6062.
Kovtunovych G., Ghosh M.C., Ollivierre W., Weitzel R.P., Eckhaus M.A., Tisdale J.F., et al. 2014. Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice. Blood, 124(9): 1522–1530.
Kowalczyk A., Kleniewska P., Kolodziejczyk M., Skibska B., Goraca A. 2015. The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis. Arch. Immunol. Ther. Exp. (Warsz), 63(1): 41–52.
Kumar D., Bhaskaran M., Alagappan L., Tori D., Yadav I., Konkimalla S., et al. 2010. Heme oxygenase-1 modulates mesangial cell proliferation by p21 Waf1 upregulation. Ren. Fail. 32(2): 254–258.
Lakhal-Littleton S., Crosby A., Frise M.C., Mohammad G., Carr C.A., Loick P.A.M., et al. 2019. Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice. Proc. Natl. Acad. Sci. U S A, 116(26): 13122–13130.
Lenoir O., Milon M., Virsolvy A., Henique C., Schmitt A., Masse J.M., et al. 2014. Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. J. Am. Soc. Nephrol. 25(5): 1050–1062.
Li P., Schmidt I.M., Sabbisetti V., Tio M.C., Opotowsky A.R., Waikar S.S. 2020. Plasma endothelin-1 and risk of death and hospitalization in patients undergoing maintenance hemodialysis. Clin. J. Am. Soc. Nephrol. 15(6): 784–793.
Liou S.F., Hsu J.H., Chen Y.T., Chen I.J., Yeh J.L. 2015. KMUP-1 attenuates endothelin-1-induced cardiomyocyte hypertrophy through activation of heme oxygenase-1 and suppression of the Akt/GSK-3beta, Calcineurin/nfatc4 and RhoA/ROCK pathways. Molecules, 20(6): 10435–10449.
Liu Y., Templeton D.M. 2015. Iron-dependent turnover of IRP-1/c-aconitase in kidney cells. Metallomics, 7(5): 766–775.
Maguire J.J., Davenport A.P. 2015. Endothelin receptors and their antagonists. Semin. Nephrol. 35(2): 125–136.
Martines A.M., Masereeuw R., Tjalsma H., Hoenderop J.G., Wetzels J.F., Swinkels D.W. 2013. Iron metabolism in the pathogenesis of iron-induced kidney injury. Nat. Rev. Nephrol. 9(7): 385–398.
McCoy R.C. 1969. Ultrastructural alterations in the kidney of patients with sickle cell disease and the nephrotic syndrome. Lab. Invest. 21(2): 85–95.
Mittal S., Agarwal P., Wakhlu A., Kumar A., Mehrotra R., Mittal S. 2016. Anaemia in systemic lupus erythematosus based on iron studies and soluble transferrin receptor levels. J. Clin. Diagn. Res. 10(6): EC08–EC11.
Moulouel B., Houamel D., Delaby C., Tchernitchko D., Vaulont S., Letteron P., et al. 2013. Hepcidin regulates intrarenal iron handling at the distal nephron. Kidney Int. 84(4): 756–766.
Nath K.A., Hebbel R.P. 2015. Sickle cell disease: renal manifestations and mechanisms. Nat. Rev. Nephrol. 11(3): 161–171.
Nemeth E., Rivera S., Gabayan V., Keller C., Taudorf S., Pedersen B.K., et al. 2004a. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113(9): 1271–1276.
Nemeth E., Tuttle M.S., Powelson J., Vaughn M.B., Donovan A. Ward D.M., et al. 2004b. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 306(5704): 2090–2093.
Opitz C.F., Ewert R., Kirch W., Pittrow D. 2008. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 29(16): 1936–1948.
Pawlak R., Berger J., Hines I. 2018. Iron status of vegetarian adults: a review of literature. Am. J. Lifestyle Med. 12(6): 486–498.
Phelan M., Perrine S.P., Brauer M., Faller D.V. 1995. Sickle erythrocytes, after sickling, regulate the expression of the endothelin-1 gene and protein in human endothelial cells in culture. J. Clin. Invest. 96(2): 1145–1151.
Poss K.D., Tonegawa S. 1997. Heme oxygenase 1 is required for mammalian iron reutilization. Proc. Natl. Acad. Sci. U S A, 94(20): 10919–10924.
Radhakrishnan N., Yadav S.P., Sachdeva A., Pruthi P.K., Sawhney S., Piplani T., et al. 2011. Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. J. Pediatr. Hematol. Oncol. 33(1): 74–78.
Raina R., Chauvin A., Chakraborty R., Nair N., Shah H., Krishnappa V., et al. 2020. The role of endothelin and endothelin antagonists in chronic kidney disease. Kidney Dis. (Basel), 6(1): 22–34.
Rhodes C.J., Wharton J., Howard L., Gibbs J.S., Vonk-Noordegraaf A., Wilkins M.R. 2011. Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur. Respir. J. 38(6): 1453–1460.
Ritz E. 2006. Anemia and diabetic nephropathy. Curr. Diab. Rep. 6(6): 469–472.
Rivera-Lebron B.N., Risbano M.G. 2017. Ambrisentan: a review of its use in pulmonary arterial hypertension. Ther. Adv. Respir. Dis. 11(6): 233–244.
Rooyakkers T.M., Stroes E.S., Kooistra M.P., van Faassen E.E., Hider R.C., Rabelink T.J., et al. 2002. Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo. Eur. J. Clin. Invest. 32(Suppl 1): 9–16.
Rosano L., Spinella F., Bagnato A. 2013. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer, 13(9): 637–651.
Ross S.L., Biswas K., Rottman J., Allen J.R., Long J., Miranda L.P., et al. 2017. Identification of antibody and small molecule antagonists of ferroportin–hepcidin interaction. Front. Pharmacol. 8: 838.
Rubio-Navarro A., Sanchez-Nino M.D., Guerrero-Hue M., Garcia-Caballero C., Gutierrez E., Yuste C., et al. 2018. Podocytes are new cellular targets of haemoglobin-mediated renal damage. J. Pathol. 244(3): 296–310.
Sabaa N., de Franceschi L., Bonnin P., Castier Y., Malpeli G., Debbabi H., et al. 2008. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J. Clin. Invest. 118(5): 1924–1933.
Schein A., Enriquez C., Coates T.D., Wood J.C. 2008. Magnetic resonance detection of kidney iron deposition in sickle cell disease: a marker of chronic hemolysis. J. Magn. Reson. Imaging, 28(3): 698–704.
Sheerin N.S., Sacks S.H., Fogazzi G.B. 1999. In vitro erythrophagocytosis by renal tubular cells and tubular toxicity by haemoglobin and iron. Nephrol. Dial. Transplant, 14(6): 1391–1397.
Smith C.P., Thevenod F. 2009. Iron transport and the kidney. Biochim. Biophys. Acta, 1790(7): 724–730.
Speed J.S., Pollock D.M. 2013. Endothelin, kidney disease, and hypertension. Hypertension, 61(6): 1142–1145.
Speed J.S., Fox B.M., Johnston J.G., Pollock D.M. 2015. Endothelin and renal ion and water transport. Semin. Nephrol. 35(2): 137–144.
Sponsel H.T., Alfrey A.C., Hammond W.S., Durr J.A., Ray C., Anderson R.J. 1996. Effect of iron on renal tubular epithelial cells. Kidney Int. 50(2): 436–444.
Tajima S., Tsuchiya K., Horinouchi Y., Ishizawa K., Ikeda Y., Kihira Y., et al. 2010. Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells. Hypertens. Res. 33(7): 713–721.
Tharaux P.L., Hagege I., Placier S., Vayssairat M., Kanfer A., Girot R., et al. 2005. Urinary endothelin-1 as a marker of renal damage in sickle cell disease. Nephrol. Dial. Transplant, 20(11): 2408–2413.
Valko M., Jomova K., Rhodes C.J., Kuca K., Musilek K. 2016. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch. Toxicol. 90(1): 1–37.
van Raaij S., van Swelm R., Bouman K., Cliteur M., van den Heuvel M.C., Pertijs J., et al. 2018. Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease. Sci. Rep. 8(1): 9353.
van Swelm R.P.L., Vos M., Verhoeven F., Thevenod F., Swinkels D.W. 2018. Endogenous hepcidin synthesis protects the distal nephron against hemin and hemoglobin mediated necroptosis. Cell Death Dis. 9(5): 550.
van Swelm R.P.L., Wetzels J.F.M., Swinkels D.W. 2020. The multifaceted role of iron in renal health and disease. Nat. Rev. Nephrol. 16(2): 77–98.
Wang H., Nishiya K., Ito H., Hosokawa T., Hashimoto K., Moriki T. 2001. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am. J. Kidney Dis. 38(5): 1038–1044.
Wang X., Mendelsohn L., Rogers H., Leitman S., Raghavachari N., Yang Y., et al. 2014. Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Kruppel-like factor. Blood, 124(6): 946–954.
Wood J.C., Cohen A.R., Pressel S.L., Aygun B., Imran H., Luchtman-Jones L., et al. 2016. Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial. Br. J. Haematol. 172(1): 122–130.
Wrighting D.M., Andrews N.C. 2006. Interleukin-6 induces hepcidin expression through STAT3. Blood, 108(9): 3204–3209.
Yachie A., Niida Y., Wada T., Igarashi N., Kaneda H., Toma T., et al. 1999. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 103(1): 129–135.
Zhang A.S., Enns C.A. 2009. Molecular mechanisms of normal iron homeostasis. Hematology Am. Soc. Hematol. Educ. Program, 207–214.
Information & Authors
Information
Published In
Canadian Journal of Physiology and Pharmacology
Volume 100 • Number 7 • July 2022
Pages: 637 - 650
History
Received: 24 January 2022
Accepted: 31 March 2022
Accepted manuscript online: 12 April 2022
Published online: 12 April 2022
Version of record online: 10 August 2022
Notes
This paper is part of the Collection for the 17th International Conference on Endothelin (ET-17) 2021.
Copyright
© 2022 The Author(s). Permission for reuse (free in most cases) can be obtained from copyright.com.
Key Words
Mots-clés
Authors
Author Contributions
MK designed the study; MK, ES, PRD, and RM carried out the experiments; MK, ES, and RM analyzed the data; MK made the figures; MK, DMP, and ES drafted and revised the paper; and all authors approved the final version of the manuscript.
Competing Interests
The authors have declared that no competing interests exist.
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Elizabeth Saurage, Parker R. Davis, Rachel Meek, David M. Pollock, and Malgorzata Kasztan. 2022. Endothelin A receptor antagonist attenuated renal iron accumulation in iron overload heme oxygenase-1 knockout mice. Canadian Journal of Physiology and Pharmacology.
100(7): 637-650. https://doi.org/10.1139/cjpp-2022-0038
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
Cited by
1. Pathophysiological characterization of the Townes mouse model for sickle cell disease
View Options
Get Access
Login options
Check if you access through your login credentials or your institution to get full access on this article.
Subscribe
Click on the button below to subscribe to Canadian Journal of Physiology and Pharmacology