Short and Dysfunctional Telomeres Sensitize the Kidneys to Develop Fibrosis

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2023 Apr 28

PMID 37118410

Authors

Sarita Saraswati

Paula Martinez

Osvaldo Grana-Castro

Maria A Blasco

Affiliations

Soon will be listed here.

Abstract

Accumulation of short telomeres is a hallmark of aging. Mutations in telomerase or telomere-binding proteins lead to telomere shortening or dysfunction and are at the origin of human pathologies known as 'telomere syndromes', which are characterized by loss of the regenerative capacity of tissues and fibrotic pathologies. Here, we generated two mouse models of kidney fibrosis, either by combining telomerase deficiency to induce telomere shortening and a low dose of folic acid, or by conditionally deleting Trf1, a component of the shelterin telomere protective complex, from the kidneys. We find that short telomeres sensitize the kidneys to develop fibrosis in response to folic acid and exacerbate the epithelial-to-mesenchymal transition (EMT) program. Trf1 deletion in kidneys led to fibrosis and EMT activation. Our findings suggest that telomere shortening or dysfunction may contribute to pathological, age-associated renal fibrosis by influencing the EMT program.

Citing Articles

The relationship between telomere length and aging-related diseases.

Huang X, Huang L, Lu J, Cheng L, Wu D, Li L Clin Exp Med. 2025; 25(1):72.

PMID: 40044947 PMC: 11882723. DOI: 10.1007/s10238-025-01608-z.

Update of cellular senescence in kidney fibrosis: from mechanism to potential interventions.

Yang L, Ma L, Fu P, Nie J Front Med. 2025; .

PMID: 40011387 DOI: 10.1007/s11684-024-1117-z.

Telomere function and regulation from mouse models to human ageing and disease.

Jones-Weinert C, Mainz L, Karlseder J Nat Rev Mol Cell Biol. 2024; .

PMID: 39614014 DOI: 10.1038/s41580-024-00800-5.

Renal fibroblasts are involved in fibrogenic changes in kidney fibrosis associated with dysfunctional telomeres.

Saraswati S, Martinez P, Serrano R, Mejias D, Grana-Castro O, Alvarez Diaz R Exp Mol Med. 2024; 56(10):2216-2230.

PMID: 39349834 PMC: 11541748. DOI: 10.1038/s12276-024-01318-8.

A cellular identity crisis? Plasticity changes during aging and rejuvenation.

Gorelov R, Hochedlinger K Genes Dev. 2024; 38(17-20):823-842.

PMID: 39293862 PMC: 11535162. DOI: 10.1101/gad.351728.124.

References

Luyckx V, Tonelli M, Stanifer J . The global burden of kidney disease and the sustainable development goals. Bull World Health Organ. 2018; 96(6):414-422D. PMC: 5996218. DOI: 10.2471/BLT.17.206441. View

Humphreys B . Mechanisms of Renal Fibrosis. Annu Rev Physiol. 2017; 80:309-326. DOI: 10.1146/annurev-physiol-022516-034227. View

Dongre A, Weinberg R . New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2018; 20(2):69-84. DOI: 10.1038/s41580-018-0080-4. View

Grande M, Sanchez-Laorden B, Lopez-Blau C, de Frutos C, Boutet A, Arevalo M . Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015; 21(9):989-97. DOI: 10.1038/nm.3901. View

Inoue T, Okada H, Takenaka T, Watanabe Y, Suzuki H . A case report suggesting the occurrence of epithelial-mesenchymal transition in obstructive nephropathy. Clin Exp Nephrol. 2009; 13(4):385-388. DOI: 10.1007/s10157-009-0168-4. View

Martinez P, Blasco M . Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017; 216(4):875-887. PMC: 5379954. DOI: 10.1083/jcb.201610111. View

de Lange T . Shelterin-Mediated Telomere Protection. Annu Rev Genet. 2018; 52:223-247. DOI: 10.1146/annurev-genet-032918-021921. View

Armanios M, Blackburn E . The telomere syndromes. Nat Rev Genet. 2012; 13(10):693-704. PMC: 3548426. DOI: 10.1038/nrg3246. View

Blackburn E . Telomere states and cell fates. Nature. 2000; 408(6808):53-6. DOI: 10.1038/35040500. View

10.

Blasco M . Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet. 2005; 6(8):611-22. DOI: 10.1038/nrg1656. View

11.

IJpma A, Greider C . Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. Mol Biol Cell. 2003; 14(3):987-1001. PMC: 151574. DOI: 10.1091/mbc.02-04-0057. View

12.

Blasco M, Funk W, Villeponteau B, Greider C . Functional characterization and developmental regulation of mouse telomerase RNA. Science. 1995; 269(5228):1267-70. DOI: 10.1126/science.7544492. View

13.

Flores I, Cayuela M, Blasco M . Effects of telomerase and telomere length on epidermal stem cell behavior. Science. 2005; 309(5738):1253-6. DOI: 10.1126/science.1115025. View

14.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

15.

Armanios M, Chen J, Cogan J, Alder J, Ingersoll R, Markin C . Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007; 356(13):1317-26. DOI: 10.1056/NEJMoa066157. View

16.

Armanios M . Telomerase mutations and the pulmonary fibrosis-bone marrow failure syndrome complex. N Engl J Med. 2012; 367(4):384. DOI: 10.1056/NEJMc1206730. View

17.

Mitchell J, Wood E, Collins K . A telomerase component is defective in the human disease dyskeratosis congenita. Nature. 1999; 402(6761):551-5. DOI: 10.1038/990141. View

18.

Tsakiri K, Cronkhite J, Kuan P, Xing C, Raghu G, Weissler J . Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007; 104(18):7552-7. PMC: 1855917. DOI: 10.1073/pnas.0701009104. View

19.

Coresh J, Astor B, Greene T, Eknoyan G, Levey A . Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2002; 41(1):1-12. DOI: 10.1053/ajkd.2003.50007. View

20.

Beier F, Foronda M, Martinez P, Blasco M . Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita. Blood. 2012; 120(15):2990-3000. PMC: 3918664. DOI: 10.1182/blood-2012-03-418038. View