Long-Term Treatment of Cyclosporine Decreases the Expression of Brain-Derived Neurotrophic Factor in Renal Collecting Duct.

Abstract

Background:Brain-derived neurotrophic factor (BDNF) is originally expressed in central nervous system, but the expression and role of BDNF in chronic cyclosporine (CsA) nephropathy has not to be illustrated. The present study examined the expression of BDNF and its receptors (tyrosine kinase receptors) on kidney in a rat model of chronic cyclosporine (CsA) nephropathy. Methods: Sprague-Dawley rats kept on a low salt diet (0.05% sodium) were treated the VH (vehicle, olive oil, 1 mL/kg s.c.) or CsA (15 mg/kg s.c.) with/without vasopressin infusion. Urine volume, renal histology, and oxidative stress (8-hydroxy-2'-deoxyguanosine,8-OHdG) were compared for different treatment groups.The expression of BDNF,tyrosine receptor kinase (Trk) B and TrkC was evaluated with immunohistochemistry, immunofluorescence, and immunoblotting. Apoptosis was also measured with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in tissue sections. Results:Four weeks treatment of CsA increased urine volume, renal fibrosis, and oxidative stress which were accompanied with the decreased BDNF, TrkB and TrkC. The expression of BDNF and TrkB and TrkC were constitutively localized in the collecting tubules in VH group, which were confirmed by double immunofluorescence with AQP-2, but these were markedly decreased in CsA treatmentin same tubular cells. CsA treatment significantly increased the number of TUNEL-positive cells and this was well correlated with the BDNF expression (r = 0.778, P < 0.01). Vasopressin-infused rat treating CsA showed the restored the urine volume and the expression of BDNF and its receptors also recovered to the normal level. Conclusion: Our observations suggest that long-term treatment of CsA inhibits BDNF and its receptor expression in the renal collecting tubule, and that this may be associated with impairment of urine concentration ability.