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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/F1563    most recent 90302.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Verzola, D. Articles by Garibotto, G. Search for Related Content PubMed PubMed Citation Articles by Verzola, D. Articles by Garibotto, G.

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

¹Department of Internal Medicine and Cardionephrology, Azienda Universitaria Ospedale San Martino, University of Genoa; ²Dipartimento di Oncologia, Biologia e Genetica, Università di Genova and Istituto Nazionale per la Ricerca sul Cancro, Genoa; ³Renal Immunopathology Centre, San Carlo Hospital, Milan, Italy; ⁴Department of Urology, University of Genoa; and ⁵Nephrology Division, Imperia Hospital, Imperia, Italy

Submitted 11 May 2008 ; accepted in final form 2 September 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 β-galactosidase (SA-β-Gal) and the cell cycle inhibitor p16^INK4A are induced in renal biopsies from patients with type 2 DN. SA-β-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-β-Gal and p16^INK4A protein. Mean telomere lengths decreased 20% as an effect of replicative senescence. In addition, mean telomere decreased further by 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.

tubular cells; telomeres; p16^INK4A; senescence-associated β-galactosidase