Summary
Impaired heparan sulphate biosynthesis through diabetes-induced inhibition of glucosaminyl N-deacetylase may have a central role in the development of diabetic nephropathy, and genetic differences in the vulnerability of the N-deacetylase could influence the risk of developing nephropathy. We studied N-deacetylase activity in fibroblast cultures from Type 1 (insulin-dependent) diabetic patients with (n = 14) or without (n = 13) diabetic nephropathy, together with non-diabetic control subjects (n = 7). No difference in N-deacetylase activity was found (p = 0.13), and no inhibition of N-deacetylase was found in cultures grown at 25 mmol/l glucose. N-deacetylase activity was inversely correlated to growth rate (r=−0.59,p=0.0008), and in patients with nephropathy a negative correlation between HbA1C and fibroblast N-deacetylase activity (r=−0.72,p = 0.012) was found. Cell-cycle analysis revealed an increased fraction of S-phase cells in patients with nephropathy (28%(21–52%)) compared to healthy control subjects (17% (9–24%)),p=0.0008, but not between patients with and without nephropathy (latter group 26%(11–43%)),p = 0.43. Forskolin, an activator of protein kinase A, specifically decreased N-deacetylase activity, whereas activation of protein kinase C produced a combined reduction in N-deacetylase activity and total protein synthesis. In conclusion, no constitutive defects in N-deacetylase activity were found in fibroblasts from these patients. Further studies should consider possible associations between fibroblast characteristics and pre-biopsy environmental parameters related to cellular memory phenomena. Finally, activation of protein kinase A provides a potential general pathway for regulating N-deacetylase activity.
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Kofoed-Enevoldsen, A., Petersen, J.S. & Deckert, T. Glucosaminyl N-deacetylase in cultured fibroblasts: comparison of patients with and without diabetic nephropathy, and identification of a possible mechanism for diabetes-induced N-deacetylase inhibition. Diabetologia 36, 536–540 (1993). https://doi.org/10.1007/BF02743270
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DOI: https://doi.org/10.1007/BF02743270