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

作者：Verzola Daniela; Gandolfo Maria Teresa; Gaetani Gianfranco; Ferraris Annamaria; Mangerini Rosa; Ferrario Franco; Villaggio Barbara; Gianiorio Fabio; Tosetti Fanny; Weiss Ursula; Traverso Paolo; Mji Mariano; Deferrari Giacomo^*; Garibotto Giacomo

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2008, 295(5): F1563-F1573.

DOI：10.1152/ajprenal.90302.2008

• tubular cells
• telomeres
• p16(INK4A)
• senescence-associated beta-galactosidase

Verzola D, Gandolfo MT, Gaetani G, Ferraris AM, Mangerini R, Ferrario F, Villaggio B, Gianiorio F, Tosetti F, Weiss U, Traverso P, Mji M, Deferrari G, Garibotto G. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. Am J Physiol Renal Physiol 295: F1563-F1573, 2008. First published September 3, 2008; doi:10.1152/ajprenal.90302.2008. -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 p16(INK4A) 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. P16(INK4A) expression was significantly increased in tubules (P < 0.005) and in podocytes (P = 0.04). Nuclear p16(INK4A) in glomeruli was associated with proteinuria (P < 0.002), while tubular p16(INK4A) 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 p16(INK4A) protein. Mean telomere lengths decreased similar to 20% as an effect of replicative senescence. In addition, mean telomere decreased further by similar to 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.

• 出版日期2008-11