ABSTRACT
DJ-1 is a redox-sensitive chaperone with reported antioxidant and anti-inflammatory properties in the kidney. The 20 amino acid (aa) peptide ND-13 consists of 13 highly conserved aas from the DJ-1 sequence and a TAT-derived 7 aa sequence that helps in cell penetration. This study aimed to determine if ND-13 treatment prevents the renal damage and inflammation associated with unilateral ureter obstruction (UUO). Male C57Bl/6 and DJ-1-/- mice underwent UUO and were treated with ND-13 or vehicle for 14 days. ND-13 attenuated the renal expression of fibrotic markers TGF-ß and collagen1a1 (Col1a1) and inflammatory markers TNF-α and IL-6 in C57Bl/6 mice. DJ-1-/- mice treated with ND-13 presented similar decreased expression of TNF-α, IL-6 and TGF-ß. However, in contrast to C57Bl/6 mice, ND-13 failed to prevent renal fibrosis or to ameliorate the expression of Col1a1 in this genotype. Further, UUO led to elevated urinary levels of the proximal tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) in DJ-1-/- mice, which were blunted by ND-13. Our results suggest that ND-13 protects against UUO-induced renal injury, inflammation and fibrosis. These are all crucial mechanisms in the pathogenesis of kidney injury. Thus, ND-13 may be a new therapeutic approach to prevent renal diseases.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Inflammation/drug therapy , Peptide Fragments/therapeutic use , Protective Agents/therapeutic use , Protein Deglycase DJ-1/therapeutic use , Ureteral Obstruction/drug therapy , Animals , Biomarkers/metabolism , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Transforming Growth Factor beta/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVE: To evaluate analgesic effects of an improved sustained-release buprenorphine (BUP-SR) formulation administered to mice. ANIMALS: 36 male Swiss-Webster mice. PROCEDURES: Mice were assigned to each of 3 treatment groups (n = 12 mice/group). Treatments were administered SC (vehicle [control treatment], 1.5 mg of buprenorphine hydrochloride [BUP-HCl]/kg, and 1.5 mg of BUP-SR/kg). Mice were evaluated (total activity, gastrointestinal tract motility, respiratory rate, cataleptic behavior, and tall-flick and hot plate nociception tests) to determine behavioral and physiologic responses at 4, 24, and 48 hours after treatment administration. Body weight and respiratory rate were measured before and at each time point after treatment administration. RESULTS: SC administration of BUP-SR resulted in significant antinociception effects for 48 hours for the hot plate and tall-flick nociception tests without substantial adverse effects. Gastrointestinal tract motility and total activity were higher at 4 hours for mice receiving BUP-SR than for mice receiving the vehicle, but values were the same between these groups at 24 and 48 hours. The BUP-SR group had a lower respiratory rate than did the control group at all times after treatment administration. Mice treated with BUP-SR had no significant changes in body weight during the study, whereas mice treated with BUP-HCl had a significant decrease in body weight at 24 and 48 hours. CONCLUSIONS AND CLINICAL RELEVANCE: BUP-SR administration resulted in antinociception effects for 48 hours. Results of this study indicated that the improved BUP-SR formulation could be safely administered SC and conferred superior analgesia, compared with that for BUP-HCl, in mice.
