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.

Abstract

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.

• Authors: A Kofoed-Enevoldsen, J S Petersen, T Deckert
• Journal: Diabetologia (Diabetologia) Vol. 36 Issue 6 Pg. 536-40 (Jun 1993) ISSN: 0012-186X [Print] Germany
• PMID: 8335176 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amidohydrolases
• N-acetylglucosamine deacetylase

Topics

• Adult
• Amidohydrolases (antagonists & inhibitors, metabolism)
• Biopsy
• Cell Cycle
• Cell Division
• Cells, Cultured
• Diabetes Mellitus, Type 1 (enzymology, pathology)
• Diabetic Nephropathies (enzymology, pathology)
• Female
• Fibroblasts (cytology, enzymology, pathology)
• Humans
• Kinetics
• Male
• Middle Aged
• Reference Values
• Skin (cytology, enzymology, pathology)