Inflammation, Senescence and MicroRNAs in Chronic Kidney Disease
Andrés Carmona, Fátima Guerrero, María José Jimenez, Francisco Ariza, Marisa L. Agüera, Teresa Obrero, Victoria Noci, Juan R. Muñoz‐Castañeda, Mariano Rodríguez, Sagrario Soriano, Juan Antonio Moreno, Alejandro Martín‐Malo, Pedro Aljama
Abstract
Background: Patients with chronic kidney disease (CKD) show a chronic microinflammatory state that promotes premature aging of the vascular system. Currently, there is a growth interest in the search of novel biomarkers related to vascular aging to identify CKD patients at risk to develop cardiovascular complications. Methods: Forty-five CKD patients were divided into three groups according to CKD-stages (predialysis (CKD4-5), hemodialysis (HD) and kidney transplantation (KT)). In all these patients, we evaluated the quantitative changes in miRNAs, CD14+C16++ monocytes number, and microvesicles (MV) concentration (both total MV, and monocytes derived MV (CD14+Annexin V+CD16+)). To understand the molecular mechanism involved in senescence and osteogenic transdifferentation of vascular smooth muscle cells (VSMC), these cells were stimulated with MV isolated from THP-1 monocytes treated with uremic toxins (txMV). Results: A miRNA array was used to investigate serum miRNA profiles in CKD patients. Reduced expression levels of miRNAs-126-3p, -191-5p and -223-3p were observed in CKD4-5 and HD patients as compared to KT. This down-regulation disappeared after KT, even when lower glomerular filtration rates (eGFR) persisted. Moreover, HD patients had higher percentage of proinflammatory monocytes (CD14+CD16++) and MV derived of proinflammatory monocytes (CD14+Annexin V+CD16+) than the other groups. In vitro studies showed increased expression of osteogenic markers (BMP2 and miRNA-223-3p), expression of cyclin D1, β-galactosidase activity and VSMC size in those cells treated with txMV. Conclusion: CKD patients present a specific circulating miRNAs expression profile associated with the microinflammatory state. Furthermore, microvesicles generated by monocytes treated with uremic toxins induce early senescence and osteogenic markers (BMP2 and miRNA-223-3p) in VSMC.