Physiological doses of homologous C-peptide prevent the development of glomerular hypertrophy, albuminuria, and glomerular hyperfiltration in rats with experimentally induced diabetes.

For the past 10-15 years all the children at our unit with insulin-dependent diabetes mellitus have been repeatedly followed-up with renal function tests. Renal biopsy, examined by light and electron microscopy, was included in the follow-up of 36 adolescents and young adults, aged 13-25 years, with a disease duration of 7-19 years. All subjects had undergone at least three renal function tests before biopsy and none had persistent microalbuminuria. Renal function was evaluated as glomerular filtration rate and effective renal plasma flow determined by clearances of inulin and para-amino hippuric acid. Glomerular filtration rate and filtration fraction were increased before and at the time of the biopsy. Glomerular basement membrane thickness (331-858 nm) and mesangial matrix volume fraction (7.4-17.1%) were increased. Long-term hyperfiltration and hyperperfusion before biopsy correlated inversely with mean glomerular volume. Increased filtration fraction before the biopsy correlated directly with mean of all HbA1c (r = 0.485, p< 0.01) and both variables correlated directly with mesangial matrix volume fraction, basement membrane thickness and structural index (r = 0.433, p < 0.01 and r = 0.626, p < 0.001, respectively). Urinary albumin excretion rate correlated directly with foot process width (r = 0.645, p < 0.001). By multiple regression analysis the most important variable for the increase in basal membrane thickness was the metabolic control while the mean of previous filtration fraction was most important for the increase in mesangial matrix volume. In conclusion, although none of the patients showed constant microalbuminuria, early diabetic structural changes were evident with basal membrane thickening and increased mesangial matrix volume. The structural changes related to long-standing hyperfiltration and poor metabolic control.

C-peptide administration in replacement dose to streptozotocin-diabetic rats serves to limit or prevent the glomerular hypertrophy and the mesangial matrix expansion seen in the post-hyperfiltration phase of early diabetic nephropathy.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopaminemetabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopaminedependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,KATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMTinhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy. Diabetes 49:1381-1389, 2000