Inflammation, Senescence and MicroRNAs in Chronic Kidney Disease

Andres Carmona; Fatima Guerrero; Maria Jose Jimenez; Francisco Ariza; Marisa L Agüera; Teresa Obrero; Victoria Noci; Juan Rafael Muñoz-Castañeda; Mariano Rodríguez; Sagrario Soriano; Juan Antonio Moreno; Alejandro Martin-Malo; Pedro Aljama

doi:10.3389/fcell.2020.00739

Inflammation, Senescence and MicroRNAs in Chronic Kidney Disease

Front Cell Dev Biol. 2020 Aug 6:8:739. doi: 10.3389/fcell.2020.00739. eCollection 2020.

Authors

Andres Carmona¹, Fatima Guerrero^{1

2}, Maria Jose Jimenez¹, Francisco Ariza¹, Marisa L Agüera^{1

3}, Teresa Obrero¹, Victoria Noci⁴, Juan Rafael Muñoz-Castañeda^{1

3}, Mariano Rodríguez^{1

2

3

5}, Sagrario Soriano^{1

3

5}, Juan Antonio Moreno^{1

6}, Alejandro Martin-Malo^{1

2

3

5}, Pedro Aljama^{1

2}

Affiliations

¹ Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, Córdoba, Spain.
² Department of Medicine, University of Córdoba, Córdoba, Spain.
³ Nephrology Unit, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.
⁴ Anesthesia Unit, Reina Sofía University Hospital, Córdoba, Spain.
⁵ Spanish Renal Research Network (REDinREN), Institute of Health Carlos III, Madrid, Spain.
⁶ Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.

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 microRNAs (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 miRNAs profile 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.

Keywords: chronic kidney disease; microRNAs; microvesicles; monocytes CD14+CD16++; vascular smooth muscle cells.