Eplerenone reduces lymphangiogenesis in the contralateral kidneys of UUO rats.
Animals
Eplerenone
/ pharmacology
Lymphangiogenesis
/ drug effects
Rats
Fibrosis
/ drug therapy
Kidney
/ metabolism
Ureteral Obstruction
/ drug therapy
Mineralocorticoid Receptor Antagonists
/ pharmacology
Male
Receptors, Mineralocorticoid
/ metabolism
Spironolactone
/ analogs & derivatives
Vascular Endothelial Growth Factor C
/ metabolism
Disease Models, Animal
Endothelial Cells
/ drug effects
Rats, Sprague-Dawley
Myofibroblasts
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
01 05 2024
01 05 2024
Historique:
received:
06
12
2023
accepted:
25
04
2024
medline:
2
5
2024
pubmed:
2
5
2024
entrez:
1
5
2024
Statut:
epublish
Résumé
Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.
Identifiants
pubmed: 38693148
doi: 10.1038/s41598-024-60636-z
pii: 10.1038/s41598-024-60636-z
doi:
Substances chimiques
Eplerenone
6995V82D0B
Mineralocorticoid Receptor Antagonists
0
Receptors, Mineralocorticoid
0
Spironolactone
27O7W4T232
Vascular Endothelial Growth Factor C
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9976Subventions
Organisme : National Natural Science Foundation Project of China
ID : 82305121
Organisme : National Natural Science Foundation Project of China
ID : 82174317
Organisme : the natural science fund of Hebei province
ID : H2023423042
Organisme : the Construction Program of new research and development platform and institution, Hebei Province Innovation Ability Promotion Plan
ID : 20567624H
Informations de copyright
© 2024. The Author(s).
Références
Carney, E. F. The impact of chronic kidney disease on global health.Nat. Rev. Nephrol.16, 1–1. https://doi.org/10.1038/s41581-020-0268-7 (2020).
doi: 10.1038/s41581-020-0268-7
pubmed: 31654043
Jha, V.et al.Chronic kidney disease: Global dimension and perspectives.The Lancet382, 260–272. https://doi.org/10.1016/s0140-6736(13)60687-x (2013).
doi: 10.1016/s0140-6736(13)60687-x
Lv, J. C. & Zhang, L. X. Prevalence and disease burden of chronic kidney disease.Adv. Exp. Med. Biol.1165, 3–15. https://doi.org/10.1007/978-981-13-8871-2_1 (2019).
doi: 10.1007/978-981-13-8871-2_1
pubmed: 31399958
Pei, G.et al.Lymphangiogenesis in kidney and lymph node mediates renal inflammation and fibrosis.Sci. Adv.5, 5075. https://doi.org/10.1126/sciadv.aaw5075 (2019).
doi: 10.1126/sciadv.aaw5075
Ma, X.et al.Eplerenone ameliorates cell pyroptosis in contralateral kidneys of rats with unilateral ureteral obstruction.Nephron142, 233–242. https://doi.org/10.1159/000497489 (2019).
doi: 10.1159/000497489
pubmed: 30799394
Wang, C.-H.et al.The inhibitory effect of eplerenone on cell proliferation in the contralateral kidneys of rats with unilateral ureteral obstruction.Nephron136, 328–338. https://doi.org/10.1159/000473702 (2017).
doi: 10.1159/000473702
pubmed: 28402979
Xiong, Y.et al.Eplerenone attenuates fibrosis in the contralateral kidney of UUO rats by preventing macrophage-to-myofibroblast transition.Front. Pharmacol. https://doi.org/10.3389/fphar.2021.620433 (2021).
doi: 10.3389/fphar.2021.620433
pubmed: 35342388
pmcid: 8727548
Guo, Y. C.et al.macrophages regulate unilateral ureteral obstruction-induced renal lymphangiogenesis through C-C motif chemokine receptor 2-dependent phosphatidylinositol 3-Kinase-AKT-mechanistic target of rapamycin signaling and hypoxia-inducible factor-1alpha/vascular endothelial growth factor-C expression.Am. J. Pathol.187, 1736–1749. https://doi.org/10.1016/j.ajpath.2017.04.007 (2017).
doi: 10.1016/j.ajpath.2017.04.007
pubmed: 28627412
Meng, X. M.et al.Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis.Cell Death Dis.7, e2495. https://doi.org/10.1038/cddis.2016.402 (2016).
doi: 10.1038/cddis.2016.402
pubmed: 27906172
pmcid: 5261004
Vernon, M. A., Mylonas, K. J. & Hughes, J. Macrophages and renal fibrosis.Seminars Nephrol.30, 302–317. https://doi.org/10.1016/j.semnephrol.2010.03.004 (2010).
doi: 10.1016/j.semnephrol.2010.03.004
Chrissobolis, S. Vascular consequences of aldosterone excess and mineralocorticoid receptor antagonism.Curr. Hypertens. Rev.13, 46–56. https://doi.org/10.2174/1573402113666170228151402 (2017).
doi: 10.2174/1573402113666170228151402
pubmed: 28245785
Pacurari, M., Kafoury, R., Tchounwou, P. B. & Ndebele, K. The renin-angiotensin-aldosterone system in vascular inflammation and remodeling.Int. J. Inflamm.2014, 689360. https://doi.org/10.1155/2014/689360 (2014).
doi: 10.1155/2014/689360
Seeger, H., Bonani, M. & Segerer, S. The role of lymphatics in renal inflammation.Nephrol. Dial. Transp.27, 2634–2641. https://doi.org/10.1093/ndt/gfs140 (2012).
doi: 10.1093/ndt/gfs140
Tammela, T. & Alitalo, K. Lymphangiogenesis: Molecular mechanisms and future promise.Cell140, 460–476. https://doi.org/10.1016/j.cell.2010.01.045 (2010).
doi: 10.1016/j.cell.2010.01.045
pubmed: 20178740
Vaahtomeri, K., Karaman, S., Mäkinen, T. & Alitalo, K. Lymphangiogenesis guidance by paracrine and pericellular factors.Genes Dev.31, 1615–1634. https://doi.org/10.1101/gad.303776.117 (2017).
doi: 10.1101/gad.303776.117
pubmed: 28947496
pmcid: 5647933
Kinashi, H., Ito, Y., Sun, T., Katsuno, T. & Takei, Y. Roles of the TGF-beta (–) VEGF-C pathway in fibrosis-related lymphangiogenesis.Int. J. Mol. Sci. https://doi.org/10.3390/ijms19092487 (2018).
doi: 10.3390/ijms19092487
pubmed: 30142879
pmcid: 6163754
Lee, A. S.et al.Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction.Kidney Int.83, 50–62. https://doi.org/10.1038/ki.2012.312 (2013).
doi: 10.1038/ki.2012.312
pubmed: 22932121
Donnan, M. D.et al.The lymphatics in kidney health and disease.Nat. Rev. Nephrol.17, 655–675. https://doi.org/10.1038/s41581-021-00438-y (2021).
doi: 10.1038/s41581-021-00438-y
pubmed: 34158633
Wu, J.et al.Lymphatic vessels enhancing adaptive immunity deteriorates renal inflammation and renal fibrosis.Kidney Dis. Basel.6, 150–156. https://doi.org/10.1159/000506201 (2020).
doi: 10.1159/000506201
pubmed: 32523957
pmcid: 7265728
Zimmer, J. K.et al.Lymphangiogenesis is upregulated in kidneys of patients with multiple myeloma.Anat. Rec. Hoboken293, 1497–1505. https://doi.org/10.1002/ar.21189 (2010).
doi: 10.1002/ar.21189
pubmed: 20648479
Jafree, D. J.et al.Beyond a passive conduit: Implications of lymphatic biology for kidney diseases.J. Am. Soc. Nephrol.31, 1178–1190. https://doi.org/10.1681/ASN.2019121320 (2020).
doi: 10.1681/ASN.2019121320
pubmed: 32295825
pmcid: 7269340
Wei, H.et al.CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis.Int. J. Biol. Sci.18, 1171–1187. https://doi.org/10.7150/ijbs.66781 (2022).
doi: 10.7150/ijbs.66781
pubmed: 35173546
pmcid: 8771854
Qiang, P.et al.Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-β1 pathway in mice induced with aldosterone.Front. Immunol. https://doi.org/10.3389/fimmu.2022.948658 (2022).
doi: 10.3389/fimmu.2022.948658
pubmed: 36389791
pmcid: 9644028
Suzuki, Y.et al.Transforming growth factor-b induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction.Kidney Int.81, 865–879. https://doi.org/10.1038/ki.2011.464 (2012).
doi: 10.1038/ki.2011.464
pubmed: 22258325
Long, D. A.et al.Restoring the renal microvasculature to treat chronic kidney disease.Nat. Rev. Nephrol.8, 244–250. https://doi.org/10.1038/nrneph.2011.219 (2012).
doi: 10.1038/nrneph.2011.219
pubmed: 22310952
Haase, V. H. Mechanisms of hypoxia responses in renal tissue.J. Am. Soc. Nephrol.24, 537–541. https://doi.org/10.1681/ASN.2012080855 (2013).
doi: 10.1681/ASN.2012080855
pubmed: 23334390
Yazdani, S.et al.Proteinuria triggers renal lymphangiogenesis prior to the development of interstitial fibrosis.PLoS One7, e50209. https://doi.org/10.1371/journal.pone.0050209 (2012).
doi: 10.1371/journal.pone.0050209
pubmed: 23189189
pmcid: 3506584
Chen, G.et al.Eplerenone inhibits UUO-induced lymphangiogenesis and cardiac fibrosis by attenuating inflammatory injury.Int. Immunopharmacol.108, 108759. https://doi.org/10.1016/j.intimp.2022.108759 (2022).
doi: 10.1016/j.intimp.2022.108759
pubmed: 35428023
Rosa, I.et al.Lymphatic endothelial-to-myofibroblast transition: A potential new mechanism underlying skin fibrosis in systemic sclerosis.Cells12, 2195. https://doi.org/10.3390/cells12172195 (2023).
doi: 10.3390/cells12172195
pubmed: 37681927
pmcid: 10486460
Yoshimatsu, Y.et al.TGF-beta and TNF-alpha cooperatively induce mesenchymal transition of lymphatic endothelial cells via activation of Activin signals.PloS One15, e0232356. https://doi.org/10.1371/journal.pone.0232356 (2020).
doi: 10.1371/journal.pone.0232356
pubmed: 32357159
pmcid: 7194440
Liu, J.et al.Lymphangiogenesis and lymphatic barrier dysfunction in renal fibrosis.Int. J. Mol. Sci.23, 6970. https://doi.org/10.3390/ijms23136970 (2022).
doi: 10.3390/ijms23136970
pubmed: 35805972
pmcid: 9267103
Georgianos, P. I. & Agarwal, R. Mineralocorticoid receptor antagonism in chronic kidney disease.Kidney Int. Rep.6, 2281–2291. https://doi.org/10.1016/j.ekir.2021.05.027 (2021).
doi: 10.1016/j.ekir.2021.05.027
pubmed: 34514191
pmcid: 8418944
Xiong, Y.et al.Eplerenone attenuates fibrosis in the contralateral kidney of UUO rats by preventing macrophage-to-myofibroblast transition.Front. Pharmacol.12, 620433. https://doi.org/10.3389/fphar.2021.620433 (2021).
doi: 10.3389/fphar.2021.620433
pubmed: 33716747
pmcid: 7943730