JNK Signalling Regulates Self-Renewal of Proliferative Urine-Derived Renal Progenitor Cells Via Inhibition of Ferroptosis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Sep 8

PMID 37681928

Authors

Lisa Nguyen

Leonie Thewes

Michelle Westerhoff

Wasco Wruck

Andreas S Reichert

Carsten Berndt

James Adjaye

Affiliations

Soon will be listed here.

Abstract

With a global increase in chronic kidney disease patients, alternatives to dialysis and organ transplantation are needed. Stem cell-based therapies could be one possibility to treat chronic kidney disease. Here, we used multipotent urine-derived renal progenitor cells (UdRPCs) to study nephrogenesis. UdRPCs treated with the JNK inhibitor-AEG3482 displayed decreased proliferation and downregulated transcription of cell cycle-associated genes as well as the kidney progenitor markers-SIX2, SALL1 and VCAM1. In addition, levels of activated SMAD2/3, which is associated with the maintenance of self-renewal in UdRPCs, were decreased. JNK inhibition resulted in less efficient oxidative phosphorylation and more lipid peroxidation via ferroptosis, an iron-dependent non-apoptotic cell death pathway linked to various forms of kidney disease. Our study is the first to describe the importance of JNK signalling as a link between maintenance of self-renewal and protection against ferroptosis in SIX2-positive renal progenitor cells.

References

Engel M, McDonnell M, Law B, Moses H . Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem. 1999; 274(52):37413-20. DOI: 10.1074/jbc.274.52.37413. View

Javelaud D, Mauviel A . Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis. Oncogene. 2005; 24(37):5742-50. DOI: 10.1038/sj.onc.1208928. View

Doll S, Porto Freitas F, Shah R, Aldrovandi M, Costa Da Silva M, Ingold I . FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019; 575(7784):693-698. DOI: 10.1038/s41586-019-1707-0. View

Tournier C, Hess P, Yang D, Xu J, Turner T, Nimnual A . Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000; 288(5467):870-4. DOI: 10.1126/science.288.5467.870. View

Falcon S, Gentleman R . Using GOstats to test gene lists for GO term association. Bioinformatics. 2006; 23(2):257-8. DOI: 10.1093/bioinformatics/btl567. View

Xie H, Sun Z, Xiao X, Liu D, Qi H, Tian G . Transient Inhibition of the JNK Pathway Promotes Human Hematopoietic Stem Cell Quiescence and Engraftment. Stem Cells Transl Med. 2022; 11(6):597-603. PMC: 9216500. DOI: 10.1093/stcltm/szac019. View

Oliveira Arcolino F, Piella A, Papadimitriou E, Bussolati B, Antonie D, Murray P . Human Urine as a Noninvasive Source of Kidney Cells. Stem Cells Int. 2015; 2015:362562. PMC: 4451513. DOI: 10.1155/2015/362562. View

Hu Z, Zhang H, Yang S, Wu X, He D, Cao K . Emerging Role of Ferroptosis in Acute Kidney Injury. Oxid Med Cell Longev. 2019; 2019:8010614. PMC: 6875218. DOI: 10.1155/2019/8010614. View

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

10.

Zhang D, Wei G, Li P, Zhou X, Zhang Y . Urine-derived stem cells: A novel and versatile progenitor source for cell-based therapy and regenerative medicine. Genes Dis. 2014; 1(1):8-17. PMC: 4234168. DOI: 10.1016/j.gendis.2014.07.001. View

11.

Zhang Y . Non-Smad pathways in TGF-beta signaling. Cell Res. 2008; 19(1):128-39. PMC: 2635127. DOI: 10.1038/cr.2008.328. View

12.

Adedoyin O, Boddu R, Traylor A, Lever J, Bolisetty S, George J . Heme oxygenase-1 mitigates ferroptosis in renal proximal tubule cells. Am J Physiol Renal Physiol. 2017; 314(5):F702-F714. PMC: 6031916. DOI: 10.1152/ajprenal.00044.2017. View

13.

Nolfi-Donegan D, Braganza A, Shiva S . Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol. 2020; 37:101674. PMC: 7767752. DOI: 10.1016/j.redox.2020.101674. View

14.

Feng H, Schorpp K, Jin J, Yozwiak C, Hoffstrom B, Decker A . Transferrin Receptor Is a Specific Ferroptosis Marker. Cell Rep. 2020; 30(10):3411-3423.e7. PMC: 7172030. DOI: 10.1016/j.celrep.2020.02.049. View

15.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

16.

Erichsen L, Thimm C, Bohndorf M, Rahman M, Wruck W, Adjaye J . Activation of the Renin-Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes. Cells. 2022; 11(7). PMC: 8997628. DOI: 10.3390/cells11071095. View

17.

Sato M, Takizawa H, Nakamura A, Turner B, Shabanpoor F, Aoki Y . Application of Urine-Derived Stem Cells to Cellular Modeling in Neuromuscular and Neurodegenerative Diseases. Front Mol Neurosci. 2020; 12:297. PMC: 6915080. DOI: 10.3389/fnmol.2019.00297. View

18.

Lima-Posada I, Portas-Cortes C, Perez-Villalva R, Fontana F, Rodriguez-Romo R, Prieto R . Gender Differences in the Acute Kidney Injury to Chronic Kidney Disease Transition. Sci Rep. 2017; 7(1):12270. PMC: 5612964. DOI: 10.1038/s41598-017-09630-2. View

19.

Conrad M, Lorenz S, Proneth B . Targeting Ferroptosis: New Hope for As-Yet-Incurable Diseases. Trends Mol Med. 2020; 27(2):113-122. DOI: 10.1016/j.molmed.2020.08.010. View

20.

Blank U, Brown A, Adams D, Karolak M, Oxburgh L . BMP7 promotes proliferation of nephron progenitor cells via a JNK-dependent mechanism. Development. 2009; 136(21):3557-66. PMC: 2761106. DOI: 10.1242/dev.036335. View