The possibility that tumor necrosis factor (TNF) and interleukin-1 (IL-1) could participate in the development of diabetic nephropathy was evaluated in streptozocin (STZ)-treated diabetic rats. Diabetic rats were divided into two groups: aminoguanidine treated group (25 mg/kg body wt, daily i.p. injection; DM-AG group) and untreated group (DM group). Non-diabetic age-matched rats were also divided into two groups with the same manner and used as controls. After twelve weeks of treatment, glomerular basement membranes (GBM) were isolated from rats of each experimental group. When thioglycollate-elicited peritoneal macrophages (M phi) from normal rats were incubated with these GBM materials, GBM from DM group induced significantly greater levels of TNF and IL-1 production than did GBM from other three groups with at doses of 2.5 to 10 mg. The TNF and IL-1 production by stimulation of GBM from the DM-AG group were similar to those from each control group. Aminoguanidine treatment significantly decreased the accumulation of advanced glycation end-products (AGEs) in GBM of diabetic rats. These findings suggest that AGE-proteins may be involved in the production of TNF and IL-1 from M phi. AGE-induced cytokines may be implicated in the development of diabetic nephropathy.

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.

No abstract

The chemical oxidative conversion of creatinine (Cr) into methylguanidine (MG) has been followed by ‘H-NMR and HPLC. By using active oxygen species generated by Fenton’s reagent (Fe²⁺ and H₂O₂) or the similar reagent (Fe³⁺ and H₂O₂), creatol (CTL), a metabolite newly isolated from the urine of uremic patients, and creatones A and B were experimentally detected in the reaction mixture and implicated as successive intermediates in the pathway from CR to MG. An alternative oxidation of Cr to demethylcreatinine (glycocyamidine) was also observed. The importance of CTL in this in vitro oxidation mechanism is discussed.

A pair of novel fluorophores (N-diacetates of crosslines A and B), (3/?,4S)-3,4-dihydroxy-5-[(1 S or 1 R,2 S,3/?)-1,2,3,4-tet ra hyd roxybutyll-1,7-bis[6-( N-acetyl-~-norleucyl )]-I ,2,3,4-tetra hyd ro-I ,7-nap ht hyrid i ni u m chloride and its epimer, were isolated from the Maillard reaction mixture of a-N-acetyl-L-lysine and D-glucose, and their properties are similar to those of fluorophores in age-and diabetes-related cross-linked proteins, and a pair of homologues derived from n-pentylamine.