Abstract 055: ND-13, a DJ-1-Derived Peptide, Protects Against the Renal Fibrosis and Inflammation Associated With Unilateral Ureter Obstruction

Abstract

Oxidative stress and inflammation are important players in the pathogenesis of cardiovascular and renal diseases. DJ-1 is a redox-sensitive chaperone that regulates the expression of several antioxidant genes. Activation of the DJ-1/Nrf2 pathway in the kidney inhibits the development and progression of several renal diseases. The 20 aa peptide ND-13 consists of 13 highly conserved aa from the DJ-1 sequence and a TAT- derived 7 aa sequence to help in cell penetration. ND-13 prevents neuronal degeneration in mice; however, its effects on kidney damage remain unknown. We hypothesized that treatment with ND-13 would prevent the renal damage and inflammation associated with unilateral ureter obstruction (UUO). C57Bl/6 mice and DJ1 -/- mice underwent UUO and were divided in 3 groups: control (no UUO), UUO+scrambled peptide (SP) or UUO+ND-13 (3 mg/kg, s.c. daily). After 14 days of treatment, urine and kidneys were collected for analysis of renal damage. ND-13 treatment prevented the development of fibrosis in C57Bl/6 mice (UUO+SP: 702±189% of control, UUO+ND-13: 264±8% of control, n=2-4/group, p<0.05), suggesting that ND-13 is protective against connective tissue deposition in the kidney. Treatment with ND-13 decreased renal mRNA expression of TNF- α ( fold change from control: 101±46 in UUO+SP; 18±7 in UUO+ND-13, n=4-5/group, p<0.05), IL-6 (6.7±2 in UUO+SP; 1.54±0.3 in UUO+ND-13, p<0.05), TGF- β ( 3.3±1.12 UUO+SP; 1.4±0.03 UUO+ND-13, p<0.05) and Colagen1 α 1 (79±16 UUO+SP; 33±3.8 in UUO +ND-13, p<0.05) in C57Bl/6 mice. In DJ1 -/- mice, treatment with ND-13 similarly decreased expression of TNF-α, IL-6 and TGF-β, but, in contrast, failed to prevent renal fibrosis or kidney expression of col1 α 1 . UUO also led to elevated urinary NGAL, marker of proximal tubular injury, in DJ-1 -/- mice and ND-13 treatment prevented that increase (71±17% UUO vs control: -18±21% UUO+ND-13 vs control, n=5/group). Our results suggest that ND-13 has protective effects on renal injury, fibrosis and inflammation, crucial mechanisms in the pathogenesis of renal disease. Thus, ND-13 treatment may be a new therapeutic approach for the prevention of renal injury, fibrosis and inflammation in renal diseases. Funded by T32DK007545 to CDM and 5P01 HL074940-10, 7R01 DK039308-31 to PAJ.