PREMATURE SENESCENCE OF SKIN FIBROBLASTS FROM INSULIN-DEPENDENT DIABETIC-PATIENTS WITH KIDNEY-DISEASE

Diabetic glomerulopathy develops in a subset only of patients with ins ulin-dependent diabetes (IDDM) and early, in its course, is characteri zed by cell hypertrophy and by excessive extracellular matrix producti on. These observations suggest that an alteration in the control of ce ll growth processes may contribute to its pathogenesis and be related to the susceptibility to kidney disease. We therefore investigated whe ther the development of diabetic nephropathy is associated with abnorm alities of cell growth and morphology. Cultured skin fibroblasts from 14 IDDM patients with nephropathy (DN) were compared with those of 10 IDDM patients without nephropathy (D) and of 14 control non-diabetic s ubjects (C). Cell volume (in arbitrary units) and total protein conten t (mu g/10,000 cells) were increased in serially passaged skin fibrobl asts of IDDM patients with nephropathy (DN = 809.5 +/- 33.1 and 1.93 /- 0.38 vs. D = 764.4 +/- 31.5 and 1.5 +/- 0.37, P = 0.005 and P = 0.0 3, respectively; vs. C = 756.2 +/- 36.3 and 1.5 +/- 0.38, P = 0.0006 a nd P = 0.03, respectively). These hypertrophic cells had a tendency to a slower duplication rate and exhibited a dissociation of the DNA and cytoplasmic cell-cycles, resulting in a higher proportion of tetraplo id cells (DN = 25 +/- 15% vs. D = 6 +/- 4%, P = 0.005; and vs. C 10 +/ - 8%, P = 0.04). The frequency of terminally differentiated post-mitot ic fibrocytes, cells specialized for extracellular matrix production, was higher in patients with nephropathy compared to that of patients w ithout nephropathy and normal controls (DN = 34 +/- 14% vs. D = 21 +/- 10%, P = 0.02; and vs. C = 19 +/- 12%, P = 0.008). That early differe ntiation was a specific feature of cells derived from patients with di abetic nephropathy was confirmed by the study of cell life-span which demonstrated that these cells aged prematurely (log rank test, chi(2) = 10,012; P = 0.0067). We conclude that an acceleration of cell aging is a peculiar feature of diabetic kidney disease and map contribute to its pathological tissue changes.