Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy

Abstract

We examined the hypothesis that senescence represents a proximate mechanism by which the kidney is damaged in type 2 diabetic nephropathy (DN). As a first step, we studied whether the senescence-associated ␤-galactosidase (SA-␤-Gal) and the cell cycle inhibitor p16INK4A are induced in renal biopsies from patients with type 2 DN. SA-␤-Gal staining was approximately threefold higher (P Ͻ 0.05) than in controls in the tubular compartment of diabetic kidneys and correlated directly with body mass index and blood glucose. P16INK4A expression was significantly increased in tubules (P Ͻ 0.005) and in podocytes (P ϭ 0.04). Nuclear p16 INK4A in glomeruli was associated with proteinuria (P Ͻ 0.002), while tubular p16INK4A was directly associated with body mass index, LDL cholesterol, and HbA1c (P Ͻ 0.001-0.05). In a parallel set of experiments, proximal tubule cells passaged under high glucose presented a limited life span and an approximately twofold increase in SA-␤-Gal and p16INK4A protein. Mean telomere lengths decreased ϳ20% as an effect of replicative senescence. In addition, mean telomere decreased further by ϳ30% in cells cultivated under high glucose. Our results show that the kidney with type 2 diabetic nephropathy displays an accelerated senescent phenotype in defined renal cell types, mainly tubule cells and, to a lesser extent, podocytes. A similar senescent pattern was observed when proximal tubule cell cultures where incubated under highglucose media. These changes are associated with shortening tubular telomere length in vitro. These findings indicate that diabetes may boost common pathways involving kidney cell senescence, thus reinforcing the role of the metabolic syndrome on biological aging of tissues. tubular cells; telomeres; p16 INK4A ; senescence-associated ␤-galactosidase AGING has been proposed to represent the failure or success of tumor-suppressor mechanisms that depend on the activities of the cyclin-dependent kinase inhibitor p16INK4A and of telomere shortening (2). It has been theorized that the high frequency of end-stage renal disease in the elderly results from an interaction between somatic cell senescence and age-associated diseases, such as hypertension and type 2 diabetes mellitus, which could hinder the limited ability of aged kidney to repair and maintain epithelial functions (24, 25). Cell senescence is characterized by an irreversible growth arrest and functional and morphological changes (2), including enhanced expression of senescence markers, such as senescence-associated ␤-galactosidase (SA-␤-Gal), and different sets of genes, including negative regulators of the cell cycle (2, 17, 18). In vitro studies support the hypothesis that diabetes may accelerate cell and organ senescence in humans. Hyperglycemia induces premature replicative senescence in human skin fibroblasts, an effect that is tightly coupled to larger cell volume in skin fibroblasts from patients with diabetic nephropathy (3, 21). In addition, a role of hyperglycemia in kidney cell senescence has been observed in ...

Telomere Length and Aging

“…From a mechanistic standpoint, Verzola et al demonstrated that telomere gets shorter when cultivated cells were introduced to high glucose level, leading them to propose that telomere shortening is due to replicative senescence. Indeed, investigation of kidney with T2DM nephropathy displays similar effects (accelerated senescence in various renal cell types under high glucose levels), suggesting diabetes may boost common pathways involving kidney cell senescence (Verzola et al, 2008). As indicated in the section on CVD, shorter Leukocyte Telomere Length could also be attributed to the high oxidative stress observed in patients with T2D (Salpea et al, 2010).…”

Neurovascular Coupling in Cognitive Impairment Associated With Diabetes Mellitus

“…65 Moreover, T2DM may enhance senescence, mainly of the tubule cells of the kidney. 66 Diabetes also enhances vascular senescence, which affects BBB permeability. Previous reports by Bouchard et al suggest that T2DM seems to accelerate the aging process of the vascular wall and that the CNS capillary bed is also a target for diabetic microangiopathy.…”

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

“…Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka‐Czernik et al ., 1997; Baker et al ., 2004; Varela et al ., 2005), high‐fat feeding (Shi et al ., 2007), diabetes (Verzola et al ., 2008), tobacco exposure (Nyunoya et al ., 2006), or atherosclerosis (Wang & Bennett, 2012), and short‐term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging‐related phenotypes (Zhu et al ., 2015a,b). However, effects of long‐term senescent cell clearance on vascular reactivity and structure with aging or chronic hypercholesterolemia remain unknown.…”