CNIO researchers demonstrate that renal fibrosis is caused by telomere shortening, paving the way for future treatment.
Researchers in the Telomeres and Telomerase Group at the Spanish National Cancer Research Center (CNIO) are seeking to treat renal fibrosis by acting on one of the causes of aging: telomere shortening. The results, published in Nature Aging, demonstrate that short telomeres are at the origin of this life-limiting disease.
Longevity.Technology: Renal fibrosis, the most common cause of kidney failure, can currently only be treated by dialysis, which is expensive, time-consuming and leaves patients susceptible to heart attacks and other cardiovascular complications. The fibrosis is excessive scarring of the renal tissue, which hardens over time, losing its functionality. The amount of kidney tissue decreases with age, kidney function diminishes with age and age is a risk factor for fibrosis, so any progress in this area would a real boon for longevity research, particularly as the incidence of renal fibrosis, which is one of the predictors of the severity of renal failure, is increasing due to an increasingly aging population.
Treating age-related diseases by acting on the causes of aging is a popular longevity research strategy, and some researchers think that by preventing, slowing or reducing the the shortening of telomeres, the protective ‘caps’ on the end of our chromosomes, progress can be made in this area.
Indeed, CNIO has already succeeded in curing pulmonary fibrosis and infarctions in mice by lengthening telomeres; to investigate whether the same occurs with renal fibrosis, the researcher used mice with short telomeres and exposed them to low doses of a kidney toxin – folic acid – that mimics the exposure of people to environmental damages throughout their lives.
Researching renal fibrosis
The researchers discovered that telomere-shortening on its own was not enough to cause renal fibrosis, which they felt was to be expected because the disease does not all elderly people. However, if mice with short telomeres were exposed to low doses of the kidney toxin, kidney fibrosis did occur. “The mice reproduced all the symptoms of the human disease,” explains Dr Maria Blasco, Director of CNIO.
“These results show the important role short telomeres play in its development, and this finding undoubtedly opens new doors for the treatment of renal fibrosis,” says the first author of the study, Sarita Saraswati, a researcher with the Telomeres and Telomerase Group at CNIO [1].
The researchers, headed by Blasco, also detail a possible link between short telomeres and kidney fibrosis in the paper. Epithelial-to-mesenchymal transition (EMT) is a crucial metabolic process and is involved in regeneration and repair. Short telomeres exacerbate EMT in the kidneys and thus promote over-regeneration and over-repair; this results in a pathological scarring of kidney tissue, or fibrosis.
“This is new – it is the first time that short telomeres have been linked to epithelial-to-mesenchymal transition…”
“This is new – it is the first time that short telomeres have been linked to epithelial-to-mesenchymal transition,” says Blasco. “Furthermore, it is an important connection because this process, and the genes that regulate it, is also involved in cancer … we specifically looked for alterations in the expression of genes involved in the epithelial-to-mesenchymal transition in our mice with short telomeres and renal fibrosis, to see if short telomeres could be the trigger for the changes in expression of these genes,” explains Blasco. “And this was indeed the case [1].”
Fine-tuning renal fibrosis research
Further exploring whether telomeres have a causal role in the renal fibrosis, the researchers created a mouse model that lacked Trf1, a protein essential for telomere function. The results showed that mice with dysfunctional telomeres also developed kidney fibrosis, which highlights, the paper reports: “the importance of proper telomere function in the protection from renal fibrosis [2].”
Because the genes involved in epithelial-to-mesenchymal transition are overexpressed in patients with kidney failure, the researchers also looked at the expression of these genes in mice that had short telomeres. As the team expected: “we found that short telomeres induce changes in the expression of genes involved in EMT [2].”
The icing on the telomere cake, was a final experiment in which the research team cultured kidney cells that had been triggered to express the gene for the telomerase enzyme, which elongates telomeres. In these cells that had restored telomeres, the epithelial-to-mesenchymal transition programme returned to normal, with the cells regaining their healthy, pre-fibrotic appearance.
“As short telomeres accumulate with ageing in the organism, it is tempting to speculate that pathological EMT programmes associated with ageing, such as cancer and different types of tissue fibrosis, may be originated at least in part by the presence of short telomeres,” the authors conclude [2].
[1] https://www.cnio.es/en/news/publications/door-to-treatment-of-renal-fibrosis-caused-by-telomere-shortening/
[2] https://www.nature.com/articles/s43587-021-00040-8
