No abstract

BackgroundDiabetic nephropathy (DN) is thought to be partially due to the injury of renal cells and the renal micro-environment by free radicals. Free radial scavenging agents that inhibit free radical damage may well prevent the development of underlying conditions such as mesangial expansion (by inhibiting extracellular matrix expression) in these patients.MethodsUsing techniques for intra-cellular delivery of peptides, we made metallothionein (MT) and superoxide dismutase (SOD), potent endogenous antioxidants, readily transducible into cell membrane and tested their protective effect against the development of DN in OLETF rats. Herein, we study antioxidant peptides for their ability to prevent oxidative damage to primary rat mesangial cells (MCs), which are important constituents of renal glomeruli.ResultsIntraperitoneal administration of these antioxidants resulted in delivery to the kidney and decreased ROS and the expression of downstream signals in renal cells and postponed the usual progression to DN. In in vitro experiments, MT and SOD were efficiently transferred to MCs, and the increased removal of ROS by MT and SOD was proportional to the degree of scavenging enzymes delivered. MT and SOD decreased three major oxidative injuries (hyperglycemia, AGE and ROS exposure) and also injuries directly mediated by angiotensin II in MCs while changing downstream signal transduction.ConclusionsThe protective effects of MT and SOD for the progression of DN in experimental animals may be associated with the scavenging of ROS by MT and SOD and correlated changes in signal transduction downstream. Concomitant administration of these antioxidant peptides may prove to be a new approach for the prevention and therapy of DN.

Because diabetic neuropathy (DN) appears to result from oxidative stress in neuronal tissues, antioxidant treatment should counteract the condition. Metallothionein (MT) and superoxide dismutase (SOD) are free-radical scavengers, but their ability to cross biological membranes is limited. Applying cell penetrating peptide technologies, we made Tat-MT and Tat-SOD constructs and tested their ability to protect PC12 cells, as surrogates of peripheral nerve cells, from various forms of oxidative damage. Tat-MT and Tat-SOD were successfully delivered to PC12 cells, and the intracellular activities of MT and SOD increased in line with the amount of protein delivered. These agents inhibited cellular damage and apoptotic signaling caused by three different types of injuries (high glucose, hypoxia, and advanced glycation end product injury). We also examined transduction of Tat-MT and Tat-SOD into Otsuka Long-Evans Tokushima fatty rats. A single ip injection of Tat-MT and Tat-SOD resulted in increased radical scavenging activity and decreased apoptosis, by inhibiting nuclear factor κB and MAPK signaling. Continuous treatment resulted in improved myelination of sciatic nerves and delayed the clinical development of DN. We conclude that effective delivery of a combination antioxidant treatment may facilitate the repair of damage in patients with DN.

STAT4 alleles and the same haplotypes might influence cytokine signalling, and therefore the development of AITD as well as T1D. These results reinforce the influence of STAT4 gene as a general autoimmune gene.

Transduction of Tat-MT and Tat-SOD proteins offers a new strategy for protecting against the development of diabetes by relieving oxidative stress.