(Press-News.org) Ageing is a common factor in many diseases. So, what if it were possible to treat them by acting on the causes of ageing or, more specifically, by acting on the shortening of telomeres, the structures that protect chromosomes? This strategy is being pursued by the Telomeres and Telomerase Group of the Spanish National Cancer Research Centre (CNIO), which has already succeeded to cure pulmonary fibrosis and infarctions in mice by lengthening telomeres. Now they take a first step towards doing the same with renal fibrosis by demonstrating that short telomeres are at the origin of this disease, which is also associated with ageing.
The new study will be published this week in the journal Nature Aging.
Renal fibrosis is the most common cause of kidney failure, a disease that can currently only be treated by dialysis. It is characterised by excessive scarring of the tissue, which hardens and loses its functionality.
"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.
The authors, headed by Maria A. Blasco, also offer a possible link between short telomeres and kidney fibrosis: a phenomenon called epithelial-to-mesenchymal transition (EMT), a basic process that is crucial to the functioning of the body and is involved in regeneration and repair. Short telomeres exacerbate EMT in the kidneys and thus promote pathological scarring of kidney tissue, i.e. fibrosis.
"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."
Although new, the finding was expected. It was known that overexpression of genes involved in the epithelial-to-mesenchymal transition could lead to renal fibrosis; on the other hand, it had also been described that patients with renal fibrosis have shorter telomeres. "So 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."
It affects more than 10% of people aged over 65
It is estimated that 11% of people over the age of 65 have moderate chronic renal failure, a potentially lethal condition whose incidence is increasing due to the ageing of the population. Kidney fibrosis is one of the predictors of the severity of renal failure.
Blasco's group at CNIO has already shown that short telomeres are at the origin of other age-related diseases, such as pulmonary fibrosis. To investigate whether the same occurs with renal fibrosis, they worked with an animal model that reproduces what, according to their hypothesis, happens in older people with pulmonary fibrosis: a mouse with short telomeres that is also exposed to low doses of a kidney toxin that mimics the exposure of people to environmental damages throughout their lives.
Telomeres are proteins that protect the ends of chromosomes when a cell divides, something that happens many times during life to -among other things- regenerate tissues. With each cell division, the telomeres become shorter until they are so short that they can no longer protect the chromosomes. Cells that are damaged this way stop dividing, and the tissue ages.
Mice mimicking human disease
In this study, the researchers observed that telomere shortening alone is not enough to cause renal fibrosis, which is to be expected because the disease does not affect 100% of elderly persons. However, if mice with short telomeres were exposed to low doses of a kidney toxin, they did develop kidney fibrosis. "The mice reproduced all the symptoms of the human disease," explains Blasco.
The toxin administered -folic acid- "is not sufficient to induce fibrosis in healthy mice, but it acts synergistically with short telomeres," the paper explains.
To determine whether telomeres do indeed play a causal role in the disease, the researchers created a mouse model that lacked Trf1, a protein that is essential for telomere function. These mice with dysfunctional telomeres also developed kidney fibrosis, "highlighting the importance of proper telomere function in the protection from renal fibrosis," the authors write.
Short telomeres that change gene expression
Aware that genes involved in epithelial-to-mesenchymal transition are overexpressed in patients with kidney failure, the authors investigated the expression of these genes in mice with short telomeres. Sure enough, "we found that short telomeres induce changes in the expression of genes involved in EMT."
As a final demonstration of the importance of telomeres in kidney fibrosis, the authors cultured kidney cells in which they expressed the gene for the telomerase enzyme, which elongates telomeres. In these cells with restored telomeres, the epithelial-to-mesenchymal transition programme returned to normal, and the cells regained their healthy, pre-fibrosis 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.
According to Saraswati, "considering the significant involvement of fibrosis in cancer, it is important to describe the origin of renal fibrosis and correlate it with the presence of short telomeres."
INFORMATION:
The study was funded by the Spanish Ministry of Science and Innovation, the National Institute of Health Carlos III, the Spanish State Research Agency, the European Research Council, the European Regional Development Fund, the Community of Madrid, the Botín Foundation and Banco Santander through Santander Universities, and World Cancer Research.
Reference Article: Short and dysfunctional telomeres sensitize the kidneys to develop fibrosis. Sarita Saraswati, Paula Martinez, Osvaldo Grana-Castro, Maria A. Blasco (Nature Aging, 2021). DOI: 10.1038/s43587-021-00040-8
Oncotarget published "Folinic acid in colorectal cancer: esquire or fellow knight? Real-world results from a mono institutional, retrospective study" which reported that the stock of therapeutic weapons available in metastatic colorectal cancer has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy.
5-Fluorouracil seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate ...
Oncotarget published "A novel isoform of Homeodomain-interacting protein kinase-2 promotes YAP/TEAD transcriptional activity in NSCLC cells" which reported that In this study, the authors show that a new HIPK2 isoform increases TEAD reporter activity in NSCLC cells.
They detected and cloned a novel HIPK2 isoform 3 and found that its forced overexpression promotes TEAD reporter activity in NSCLC cells.
Expressing HIPK2 isoform 3_K228A kinase-dead plasmid failed to increase TEAD reporter activity in NSCLC cells.
Next, they showed that two siRNAs targeting HIPK2 decreased HIPK2 isoform 3 and YAP protein levels in NSCLC cells.
In summary, this Oncotarget study indicates that HIPK2 isoform 3, the main HIPK2 isoform ...
The cover for issue 51 of Oncotarget features Figure 5, "miR-4287 overexpression regulates EMT in prostate cancer cell lines," published in "MicroRNA-4287 is a novel tumor suppressor microRNA controlling epithelial-to mesenchymal transition in prostate cancer" by Bhagirath, et al. which reported that the authors analyzed the role of miR-4287 in PCa using clinical tissues and cell lines.
Receiver operating curve analysis showed that miR-4287 distinguishes prostate cancer from normal with a specificity of 88.24% and with an Area under the curve of 0.66. Further, these authors found that miR-4287 ...
NEW YORK, NY (March 15, 2021)--A cytokine "hurricane" centered in the lungs drives respiratory symptoms in patients with severe COVID-19, a new study by immunologists at Columbia University Vagelos College of Physicians and Surgeons suggests.
Two cytokines, CCL2 and CCL3, appear critical in luring immune cells, called monocytes, from the bloodstream into the lungs, where the cells launch an overaggressive attempt to clear the virus.
Targeting these specific cytokines with inhibitors may calm the immune reaction and prevent lung tissue damage. Currently, one drug that blocks immune responses to CCL2 is being studied in clinical trials of patients with severe COVID-19.
Survivors of severe COVID-19, the study also found, had a greater abundance of antiviral T cells in their lungs ...
Philadelphia, March 15, 2021 - Biomarker testing surveys specific disease-associated molecules to predict treatment response and disease progression; however its use has complicated the diagnosis of non-small-cell lung cancer (NSCLC). In a new study in The Journal of Molecular Diagnosis, published by Elsevier, investigators provide for the first time a complete overview of biomarker testing, spanning multiple treatment lines, in a single cohort of patients.
Using exploratory data analysis and process-mining techniques in a real-world setting, investigators identified significant variation in test utilization and treatment. They also found that while ...
BOSTON - Researchers at Massachusetts General Hospital (MGH) have uncovered new clues that add to the growing understanding of how female mammals, including humans, "silence" one X chromosome. Their new study, published in Molecular Cell, demonstrates how certain proteins alter the "architecture" of the X chromosome, which contributes to its inactivation. Better understanding of X chromosome inactivation could help scientists figure out how to reverse the process, potentially leading to cures for devastating genetic disorders.
Female mammals have two copies of the X chromosome in all of their cells. Each X chromosome contains many genes, but only one of the pair ...
Ingo Burgert and his team at Empa and ETH Zurich has proven it time and again: Wood is so much more than "just" a building material. Their research aims at extending the existing characteristics of wood in such a way that it is suitable for completely new ranges of application. For instance, they have already developed high-strength, water-repellent and magnetizable wood. Now, together with the Empa research group of Francis Schwarze and Javier Ribera, the team has developed a simple, environmentally friendly process for generating electricity from a type of wood sponge, as they reported last week in the journal Science Advances.
Voltage through deformation
If you want to generate electricity ...
AUSTIN, Texas -- Using NASA satellite images and machine learning, researchers with The University of Texas at Austin have mapped changes in the landscape of northwestern Belize over a span of four decades, finding significant losses of forest and wetlands, but also successful regrowth of forest in established conservation zones that protect surviving structures of the ancient Maya.
The research serves as a case study for other rapidly developing and tropical regions of the globe, especially in places struggling to balance forest and wetland conservation with agricultural needs and food security.
"Broad-scale global studies show that tropical deforestation and wetland destruction is occurring ...
Modeling - Urban climate impacts
Researchers at Oak Ridge National Laboratory have identified a statistical relationship between the growth of cities and the spread of paved surfaces like roads and sidewalks. These impervious surfaces impede the flow of water into the ground, affecting the water cycle and, by extension, the climate.
"We've shown that there is a specific mathematical shape to the relationship between a city's population and the total paved area," ORNL's Christa Brelsford said. "Using that, we examined climate model predictions and determined they correctly represent some important attributes ...
In order to withstand the rigors of space on deep-space missions, food grown outside of Earth needs a little extra help from bacteria. Now, a recent discovery aboard the International Space Station (ISS) has researchers may help create the 'fuel' to help plants withstand such stressful situations.
Publishing their findings to END ...
