Gene discovery highlights connection between the kidneys and cardiovascular disease
![Kidney image. About 80% of chronic kidney disease patients actually die from cardiovascular complications. Although the link between these diseases is well established, the actual biological mechanism involved has not been fully understood. But researchers at Temple University recently uncovered a key piece to this connection, where chronic kidney disease and high-fat diets combine to trigger blood vessel inflammation. Their findings are published online in Redox Biology.[1]](/sites/default/files/styles/top_stories/public/assets/articles/Kidney-Renal.jpg.webp?itok=MTRIpWbW)
About 80% of chronic kidney disease patients actually die from cardiovascular complications. Although the link between these diseases is well established, the actual biological mechanism involved has not been fully understood. But researchers at Temple University recently uncovered a key piece to this connection, where chronic kidney disease and high-fat diets combine to trigger blood vessel inflammation. Their findings are published online in Redox Biology.[1]
The discovery offers new clues for preventing cardiovascular disease in at-risk patients. The study describes a key mechanism involving harmful byproducts that build up when kidney function declines. These byproducts, known as uremic toxins, activate specialized sensors in cells called uremic toxin receptors. When combined with metabolic stress caused by high cholesterol, these activated receptors fuel inflammation and over activate the immune system. The researchers said these are key drivers in the development of cardiovascular disease.
“Our findings reveal how changes in cell metabolism and increased oxidative stress can activate damaging pathways in blood vessels. This helps explain why inflammation and immune dysfunction are so common in people with both kidney disease and high cholesterol," explained Xiaofeng Yang, MD, PhD, FAHA, MS, senior investigator on the study and professor and associate director of the Lemole Center for Integrated Lymphatics at the Lewis Katz School of Medicine at Temple, in a statement.
The study focused on a gene known as NR1H3, which previous research showed being overactive in the blood vessels and immune cells of people with chronic kidney disease. Activity of this gene is triggered by oxysterols—oxidized lipids derived from cholesterol that accumulate in the presence of kidney dysfunction and are known to promote inflammation.
“Little is known, however, about how lipids and NR1H3 influence chronic kidney disease or worsen cardiovascular disease. We aimed to understand how they are connected,” Yang explained.
Researchers used a mouse model of chronic kidney disease, where mice were fed a high fat diet to fuel the development of cardiovascular disease. After several months, researchers examined the animals’ aorta and used RNA sequencing to evaluate changes in the expression of inflammatory genes in aortic tissues. These were compared to inflammatory gene expression in aortas from healthy mice and from mice with only chronic kidney disease or a high fat diet.
The team found many more inflammatory genes were upregulated in mice with a combination of kidney disease and increased lipid levels resulting from high fat intake. Yang said the high levels of inflammatory signaling and the influx of inflammatory cells damaged the aortic structure. Specifically, NR1H3 was noticeably upregulated.
The study also found that a new protein, YBX2, was found toplay an essential role in preventing oxidative stress. Researchers said when its levels are decreased, levels of reactive oxygen species (ROS) increase in cells. But higher levels of YBX2 suppressed ROS, along with the activity of more than two dozen pro-inflammatory genes.
Next steps for Yang's team are to explore how targeting NR1H3, YBX2, or their related pathways might help prevent inflammation and blood vessel damage in chronic kidney disease, which could lead to new treatments not only for kidney disease-related cardiovascular complications, but also for other inflammatory conditions linked to high cholesterol and aging.
Cardiovascular-kidney-metabolic (CKM) syndrome is an area of research that has explored in the past fewer years studies continue to show how closely interconnected heart disease and kidney disease are, and how CKM is a major risk factor for increasing heart disease, stroke and peripheral artery disease. The American Medical Association (AHA) Cardiovascular-Kidney-Metabolic Health Initiative was recently expanded to 15 regions in the United States to boost awareness, screen more patients and increase treatment. It has also been a major topic of discussion at AHA and other cardiology meetings.
Read more or watch the video interview for more on CKM — Interest rising in CKM syndrome as connections become clearer, an interview with Joshua Joseph, MD, at The Ohio State University Wexner Medical Center.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: [email protected]