Platelets from patients with chronic kidney disease induced senescence in healthy donors’ killer T-cells in culture; the authors propose that the platelets transfer a microRNA, a short RNA that disrupts mitochondrial function
Platelets from patients with chronic kidney disease induced senescence in healthy donors’ killer T-cells in culture; the authors propose that the platelets transfer a microRNA, a short RNA that disrupts mitochondrial function
On October 16, nephrologists in Chongqing published a study in Experimental & Molecular Medicine involving 75 patients with stage 3–5 chronic kidney disease and 45 healthy participants. The patients’ platelets release microparticles, small vesicles containing microRNA. Healthy donors’ T-cells took up these particles in culture and became senescent. Both an inhibitor of this microRNA and NMN reduced senescence. Cells use NMN to make NAD+, a molecule they need to produce energy.
Infections are a leading cause of death in kidney disease, and T-cells help defend against them. In 2011, researchers in the Netherlands found that the T-cells of patients aged 25–45 with end-stage kidney disease resembled those of healthy people aged 60–80. The Chongqing group examined whether patients’ T-cells were exhausted or senescent relative to those of healthy people of the same age: exhausted cells express inhibitory receptors, whereas senescent cells have irreversibly stopped dividing because of DNA damage.
Published gene expression data from blood cells of patients with end-stage kidney disease showed that inhibitory receptor genes had similar activity to those in healthy people, while senescence-associated genes were more active, particularly in CD8 T-cells, or killer T-cells. In the study participants’ blood, patients had a higher proportion of CD8 T-cells expressing CD57, a protein used as a marker of senescent cells, than healthy participants did. Dialysis and cytomegalovirus, which is associated with senescence in these cells, could have explained the difference. However, the patients were not receiving dialysis, none of the participants had antibodies to the virus, and age did not differ between the groups.
The authors focused on platelets because of an earlier study: platelets are overactive in mice with kidney disease, and indoxyl sulfate, a toxin that accumulates in the blood, increases the number of platelet microparticles in vitro. The researchers cultured healthy donors’ CD8 T-cells with platelets from either patients or healthy donors. By the fifth day, only T-cells cultured with patients’ platelets had become senescent. Mitochondrial dysfunction began on the third day, before senescence developed. An antioxidant prevented both mitochondrial dysfunction and senescence, leading the authors to propose that mitochondrial dysfunction triggers senescence.
The microparticles themselves also induced senescence. They were more abundant in patients’ blood, and T-cells took them up, but only particles from patients induced senescence. Of the five microRNAs with the largest increases in patients’ microparticles, only miR-550a-5p induced senescence when introduced into T-cells. Patients’ T-cells contained more of this microRNA than those of healthy donors, and levels rose in healthy donors’ T-cells after contact with patients’ platelets. The authors interpret this as evidence of transfer.
To investigate how the microRNA affects mitochondria, the authors used databases to identify genes encoding mitochondrial proteins that it might suppress. They then examined PMPCB, a gene encoding an enzyme that cleaves proteins imported into mitochondria to produce their functional forms. Patients’ T-cells had lower levels of PMPCB, and the microRNA bound to RNA transcribed from this gene. Experimentally suppressing PMPCB reproduced senescence, while increasing PMPCB levels reduced the microRNA’s effects. This enzyme also cleaves NDUFS8, a protein that forms part of the mitochondria’s energy-producing machinery. In patients’ T-cells, NDUFS8 remained incompletely processed, and NAD+ levels were lower. The same changes occurred in healthy donors’ cells after contact with patients’ platelets, and increasing PMPCB levels reduced both changes.
Because NAD+ levels were lower, the researchers added NMN to the culture. It reduced the mitochondrial dysfunction and senescence induced by patients’ platelets. In mice given a synthetic copy of the microRNA, CD8 T-cells became senescent, and NMN reduced senescence.
The authors suggest that drugs that inhibit platelet activity, such as aspirin, might reduce CD8 T-cell senescence.