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Researchers at UVA Health and Mount Sinai have unlocked why more than half the people with chronic kidney disease ultimately die of cardiovascular issues.
Uta Erdbrügger, MD, an internal medicine physician-scientist with the University of Virginia School of Medicine’s Division of Nephrology, and colleagues have found, according to a UVA Health release, “culprit: particles called ‘circulating extracellular vesicles’ produced in diseased kidneys” that ultimately poison the heart.
Extracellular vesicles are produced by almost all cells and serve as important messengers by carrying proteins and other materials to other cells. But the extracellular vesicles produced in kidneys with CKD carry small, non-coding RNA called miRNA that are toxic to the heart, the researchers determined according to the release.
The researchers say the discovery could let doctors identify people at risk and develop new treatments to help prevent and treat heart failure for these patients.
Circulating hCKD-EVs are cardiotoxic in vitro and in vivo
A, Study design for EV isolation and characterization. B, Dynamic light scattering (DLS) analysis of EV size. C, Western blotting (WB) of EV-positive markers (Alix, Flot1, CD81, and CD63) for EVs (n=6). D, Nanoflow cytometry analysis of tetraspanins (CD9, CD63, and CD81) for EVs (n=3). E, Cryo- electron microscopy (EM) of human plasma EVs. F, Viability of hAC16-CMs treated with equal amounts of protein (200 µg/mL) from EV-enriched or EV-depleted plasma after 48 hours (n=6–12) using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. G, Study design for EV functional analysis in vitro. H and I, Representative image of live/dead assay and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay of hAC16-CMs treated with hCKD-EVs and hCtr-EVs. J and K, Quantification of live/dead assay and TUNEL assay (n=5–12). L and M, IonOptix analysis showing calcium transients and contractility of rat primary cardiomyocytes treated with hCKD-EVs and hCtr-EVs (n=5 or 6). N, Study design for EV functional analysis in vivo. O, Intramyocardial injection (IMCI) of hCKD-EVs labeled with PKH67 dye showing EV uptake in NOD/Scid mice heart. P, Representative image of TUNEL assay in NOD/Scid hearts injected with hCKD-EVs and hCtr-EVs. Q, Quantification of TUNEL+ve cells in mice hearts injected with hCKD-EVs or hCtr-EVs (n=3 or 4). Data in D are presented as median with interquartile range and were analyzed with Mann-Whitney U test. Data in F, J, K, M, and Q are presented as mean±SEM and were analyzed using Student t test. CKD indicates chronic kidney disease; Ctr, control; EVs, extracellular vesicles; hCKD-EV, plasma EVs from patients with CKD; hCtr-EV, plasma EVs from healthy controls; NTA, nanoparticle tracking analysis; and SSC, side scatter.
In lab mice, blocking the extracellular vesicles from circulating significantly improved heart function and alleviated heart failure. The scientists also looked at blood plasma samples donated by patients with CKD and by healthy patients and confirmed the presence of harmful extracellular vesicles in the CKD patients.
“Kidney and heart disease can develop silently, so they are often discovered only after damage has already been done,” Dr. Erdbrügger said. “Our findings can help to identify patients at risk for heart failure earlier, enabling earlier treatment and improved outcomes.”
Chronic kidney disease affects more than 1 in 7 Americans, approximately 35 million people in the United States, according to the National Institutes of Health. About 1 in 3 patients with diabetes and about 1 in 5 people with hypertension (high blood pressure) have kidney disease, the agency reports.
The link between chronic kidney disease (CKD) and cardiovascular problems has been well documented, with the severity of cardiovascular disease correlating directly with CKD. But scientists have struggled to understand why, partly because shared risk factors such as obesity and hypertension muddy the waters when it comes to determining cause and effect.
Scientists had, until now, been unable to pinpoint any kidney-specific risk factor that could be causing toxicity in the heart.
“Doctors always wondered how organs such as the kidney and heart communicate with each other. We show that EVs from the kidney can travel to the heart and be toxic,” Erdbrügger said. “We are just at the beginning to understand this communication.”
The results, she said, suggest that scientists may be able to develop a blood test to identify CKD patients at high risk for serious heart problems. They also may be able to target the circulating extracellular vesicles to treat or prevent the poisonous effects on the heart.
“Our hope is to develop novel biomarkers and treatment options for our kidney patients at risk for heart disease,” she said. “Potentially our work will improve precision medicine for CKD and Heart failure patients, so that each patient gets the exact treatment they need.”
Erdbrügger is organizing a hands-on workshop for UVA scientists specifically to advance extracellular vesicle research.
The five-day workshop begins Feb. 7.
Source – UVA Health
