Hiperfosfatemia y envejecimiento en sistemas renales y cardiovasculares. Papel de ILK

Abstract

During the aging process, changes lead to a functional impairment of the organs, being the kidney and the vasculature some of the most susceptible. The mechanisms involved in the aging process are under study now at days. The aging process can be accelerated or delay by environmental factors including phosphate. In a population study, the high blood phosphate levels have been inversely correlated with the lifespan from different species. Also hyperphosphatemia is observed in premature aging animal models, such as FGF23 and Klotho knocked out mice. At the cellular level, the aging process is known as cellular senescence. Cellular senescence is a permanent and irreversible cell growth arrest, which maintains cell viability and metabolic activity. Senescence process can be due to a progressive shortening of telomeres or prematurely induced by various stimuli through cellular pathways p53-p21 and p16INK4a. In vivo studies have shown that aging rat kidneys have elevated levels of p16INK4a, suggesting that senescence can be the onset of aging kidney. Integrin-linked kinase (ILK) is an intracellular effector between cell and the extracellular matrix that plays a central role in the transduction of many biochemical signals which are initiated by cell-matrix interactions that regulate fundamental processes such as growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. After a previous study where it was found that aging rat kidneys showed high levels of ILK, it raised the possibility that ILK may be carrying out an important role in aging and cell senescence. In cardiomyocyte cultures was observed that overexpression of ILK was correlated with increased expression of p53 and p21. The present work proposes ILK as a key player in the vascular and renal senescence and aging induced by high phosphate levels. We show that 15 months old mice, which show signs of aging, got hiperphosphatemia, cellular senescence and high ILK levels in the renal cortex, with a positive correlation between ILK and phosphate levels in plasma. Since the vascular cells are highly exposed to the blood phosphate levels, we determined if high phosphate levels were inducing cellular senescence in the vascular cells and the implication of ILK. High phosphate levels induce senescence in human aortic smooth muscle cells via ILK-dependent p53-p21 and p16INK4a. The increase of ILK levels induces oxidative stress through the PI3K-Akt-FoxO axis that finally lead the senescence induction. We also show that other senescence stimuli such as glycated albumin and glucose oxidase induce cellular senescence in human mesangial cells and mouse tubular cells via p53 pathway ILK dependent manner. In summary, ILK regulates the cellular senescence induced by different stimuli, supporting the importance of ILK in the renal and vascular aging process.