Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy.
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 beta-galactosidase (SA-beta-Gal) and the cell cycle inhibitor p16INK4A are induced in renal biopsies from patients with type 2 DN. SA-beta-Gal staining was approximately threefold higher (P < 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 < 0.005) and in podocytes (P = 0.04). Nuclear p16INK4A in glomeruli was associated with proteinuria (P < 0.002), while tubular p16INK4A was directly associated with body mass index, LDL cholesterol, and HbA1c (P < 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-beta-Gal and p16INK4A protein. Mean telomere lengths decreased approximately 20% as an effect of replicative senescence. In addition, mean telomere decreased further by approximately 30% 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 high-glucose 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.
Verzola
Daniela
D
Department of Internal Medicine and Cardionephrology, Azienda Universitaria Ospedale San Martino, University of Genoa, Italy.
Gandolfo
Maria Teresa
MT
Gaetani
Gianfranco
G
Ferraris
Annamaria
A
Mangerini
Rosa
R
Ferrario
Franco
F
Villaggio
Barbara
B
Gianiorio
Fabio
F
Tosetti
Fanny
F
Weiss
Ursula
U
Traverso
Paolo
P
Mji
Mariano
M
Deferrari
Giacomo
G
Garibotto
Giacomo
G