Mecanismos de senescencia en células mesangiales humanas en la diabetes y el envejecimiento

Résumé

Renal aging is associated with alterations in renal morphology and a decline in renal function, which could be accelerated and/or accentuated by diseases such as diabetes mellitus and hypertension. The diabetic nephropathy is one of the major microvascular complications in diabetes. Numerous in vitro and in vivo studies demonstrate that mesangial cells are intimately involved in glomerulosclerosis, a manifestation of end stage renal disease in diabetic nephropathy. Mesangial cells hypertrophy, basement membrane thickening and mesangial matrix expansion are among the earliest pathological features of diabetic nephropathy. Cellular senescence was first used to describe the phenotype of permanent and irreversible growth arrest in in vitro studies of human fibroblast. Senescent cells remain viable but show altered morphology, greater heterogeneity, developed hypertrophy, expression of SA-β-gal, accumulation of lipofuscin granules, and lack of response to mitogenic stimuli. Cellular senescence is accompanied in humans by loss of telomeres and DNA repeats at the ends of the chromosomes as a result of lack of telomerase activity. However, cellular senescence can also be induced prematurely in response to various physiologic stressors independent of the number of cell divisions through the p16INK4a or p53-p21 signaling pathways. Some features of senescence in aging kidney, such as the appearance of SA-β-gal and p16INK4a, are present even without morphologic changes, suggesting that some aspects of cell senescence are common in the aging kidney. The senescent cell shows some similarities with hypertrophy cell, and one of the major morphological changes in diabetic kidney is the glomerular hypertrophy. Moreover, in experimental models of diabetic nephropathy is common the presence of glomerular hypertrophy with a p21 protein increases. We propose that cellular senescence could have an important role in the development of kidney complications in diabetes and aging. High glucose concentration and advanced glycation end products are two of the main factors in diabetes eliciting pathological responses of mesangial cells and contributing to the development of renal complications in diabetes. Thereby, our aim was determinate the contribution of high glucose concentracion and advanced glycation end products to cellular senescence in human mesangial cells and analyze the intracellular mechanism involved in this process. In our experiments we demonstrate that both high glucose and glycated albumin induced cellular senescence in human mesangial cells. Nevertheless, the mechanisms of the cellular senescence were different. We show that high glucose induced cellular senescence by a hyperosmolar stress response through p53-p21 and p16INK4a signaling pathways. These effects were depending on reactive oxygen species production, oncogenic Ras and the mitogen-activated protein kinases ERk1/2 and p38 activation. Diabetic and mannitol-treated rats show an increase in both p53 and p16INK4a in glomeruli even without renal failure. These results suggest that cellular senescence could be an important factor in the development of diabetic nephropathy through a mild increment in extracellular osmolarity. Glycated albumin is one of the major advanced glycation end products in serum and it has been shown to accumulate during aging and related pathologies, such as Alzheimer disease and diabetes mellitus. We demonstrated that glycated albumin binds to the receptor of advanced glycation end products and induces cellular senescence in human mesangial cells through p53-p21 signal pathway. The release of the insulin-like growth factor 1 induced by glycated albumin and the autophosphorilation of its receptor promote the Ras-Erk1/2 pathway activation. This event induces the downregulation of the antioxidant enzyme catalase and the increase of reactive oxygen species which is responsible of the p53 increment and the senescence induction. In summary, high glucose concentrations and glycated albumin induces cellular senescence in human mesangial cells which in part could contribute to the development of diabetic nephropathy.