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Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis

Nature Aging volume 1, pages 269–283 (2021)Cite this article

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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.

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Fig. 1: A mouse model of kidney fibrosis is associated with short telomeres.
Fig. 2: Severe kidney dysfunction in telomerase-deficient mice treated with a sublethal dose of folic acid.
Fig. 3: Telomerase-deficient mice show collagen deposition and activated myofibroblasts in the kidney after a sublethal dose of folic acid.
Fig. 4: Increased kidney apoptosis and senescence in telomerase-deficient mice after a sublethal dose of folic acid.
Fig. 5: Short telomeres induce tubular damage and immune infiltration in kidney.
Fig. 6: Hyperactivation of EMT and TGFβ-signaling pathways in telomerase-deficient mice.
Fig. 7: Trf1 deletion induces renal fibrosis.
Fig. 8: TERT activation rescued the EMT phenotype in vitro.

Data availability

RNA-seq data have been deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus under accession GSE162447 (subseries GSE162445 and GSE162446). The Molecular Signatures database used in the study is available at https://www.gsea-msigdb.org/gsea/msigdb/. All other data supporting the findings of this study are available from the corresponding author upon request.

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Acknowledgements

Research in the Blasco laboratory is funded by the Spanish State Research Agency, Ministry of Science and Innovation, cofounded by the European Regional Development Fund (AF2017-82623-R and SAF2015-72455-EXP), the Comunidad de Madrid Project (S2017/BMD-3770), the World Cancer Research Project (16-1177), the European Research Council (SHELTERINS GA882385) and the Fundación Botín (Spain).

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Authors and Affiliations

  1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre, Madrid, Spain

    Sarita Saraswati, Paula Martínez & Maria A. Blasco

  2. Bioinformatics Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre, Madrid, Spain

    Osvaldo Graña-Castro

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  1. Sarita Saraswati
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  2. Paula Martínez
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Contributions

M.A.B. secured funding and conceived the original idea, designed and interpreted results, and wrote the paper. P.M. designed and interpreted results and contributed to writing the paper. S.S. designed, performed and interpreted experiments and contributed to writing the paper. O.G.-C. analyzed the RNA-seq data.

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Correspondence to Maria A. Blasco.

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Peer review information Nature Aging thanks Zhaoyong Hu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Extended Data Fig. 1 Telomerase-deficient mice with short telomeres do not spontaneously develop renal fibrosis.

a, Scheme of the experimental approach. b-f, Representative images and quantification of Masson trichrome (b), Sirius Red (c), PAS-Diastase (d), SMA (e) and E-cadherin (f) in Tert+/+ and G3Tert−/− mice. g-h, Representative images and quantification of p21 (g) and CC3 (h) immunohistochemistry stainings in Tert+/+ and G3Tert−/− mice. Insets show amplified images. A t-test two tailed was used for statistical analysis. Data is presented as mean values +/- SEM. The number of mice analyzed per genotype is indicated.

Extended Data Fig. 2 Blood parameters.

Blood creatinine (a) and blood urea nitrogen (BUN) (b) levels of untreated and FA treated Tert+/+ and G3Tert−/− mice. Blood samples were collected at days 2, 7 and 14. Mice were sacrificed at day 14. a, Two-way Anova with post hoc Bonferroni test was used for statistical analysis. Data is presented as mean values +/- SEM. The number of mice analyzed per genotype is indicated. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.

Extended Data Fig. 3 Effect of short telomeres on cell cycle regulators.

Relative expression of CCnd1, CCnd2, CCnb1 and CCne1 in Tert+/+, FA-treated Tert+/+, G3Tert−/− and FA-treated G3Tert−/− mice 14 days after administration of a low dose of FA. One-way Anova was used for statistical analysis. Data is presented as mean values +/- SEM. The number of mice analyzed per genotype is indicated. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.

Extended Data Fig. 4 Effect of shorter telomeres on EMT related genes.

a, Gene expression data obtained by RNA-seq of kidney samples from 7- and 47-week old Terc+/+ and G3 Tert−/− mice. b, Gene Set Enrichment Analysis (GSEA) plots for the EMT pathway. False Discovery Rates (FDR) are indicated. Samples correspond to kidneys of five independent Tert+/+, G3 Tert−/− mice.

Extended Data Fig. 5 Effect of shorter telomeres on nephric‐progenitor genes.

a, Relative expression of Sox-9, Wt-1, Pax-2, Sall2, Acvr2b, Klotho in in Tert+/+, FA-treated Tert+/+, G3Tert−/− and FA-treated G3Tert−/− mice 14 days after administration of a low dose of FA. b, Representative images and quantification of Sox-9 immunohistochemistry staining. The insets show amplified images. One-way Anova was used for statistical analysis. One-way Anova was used for statistical analysis. Data is presented as mean values +/- SEM. The number of mice analyzed per genotype is indicated. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001

Extended Data Fig. 6 Effect of shorter telomeres on Notch-targeted genes.

Relative expression of Notch1, 2, 3, Jagged1 and Tfam in Tert+/+, FA-treated Tert+/+, G3Tert−/− and FA-treated G3Tert−/− mice 14 days after administration of a low dose of FA. One-way Anova was used for statistical analysis. Data is presented as mean values +/- SEM. The number of mice analyzed per genotype is indicated. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.

Extended Data Fig. 7 TERT activation rescued the EMT phenotype in vitro.

a,b, Microscopic bright field images of proximal tubule cell (PTC) culture at day 8 (a) and day 14 post-transduction with either the empty or the mTert containing vector (b). c, Representative images of Immunofluorescence for E-Cadherin, SMA and Tgfβ1. Twenty micrographs were captured from each condition.

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Saraswati, S., Martínez, P., Graña-Castro, O. et al. Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis. Nat Aging 1, 269–283 (2021). https://doi.org/10.1038/s43587-021-00040-8

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