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-β 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-β. 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.
Highlights
Renal oxidative stress and inflammation are two of the most important factors involved in the pathogenesis of renal diseases and other cardiovascular disease complications [1]
Because ureter obstruction (UUO) is a classical model of progressive renal fibrosis, we evaluated by RT-PCR the expression levels of markers of fibrosis in the cortex of wild type (WT) mice that underwent sham or UUO surgery and were treated with ND-13 or vehicle for 14 days
We found that after UUO surgery, WT mice treated with vehicle presented a significant upregulation of the markers of fibrosis Col1a1 and TGF-β (~70-fold increase for Col1α1 and ~7-fold increase for TGF-β p < 0.05; Figure 1) in the renal cortex
Summary
Renal oxidative stress and inflammation are two of the most important factors involved in the pathogenesis of renal diseases and other cardiovascular disease complications [1]. Inflammation, the consequent oxidative stress, and vice versa, are considered major factors triggering fibrosis, and are key components in the development and progression of renal failure [2]. The inflammatory response during the initial stages of renal disease is characterized by glomerular and tubulo-interstitial infiltration of immune cells, including neutrophils and macrophages [4]. Macrophages are a major source of TGF-β in fibrotic organs [5,6], and recruitment of T and B lymphocytes to the site of injury further facilitates the secretion of fibrogenic cytokines [7,8]. Renal inflammation plays a central role in the initiation and progression of fibrosis in chronic kidney disease. Attenuation of the inflammatory response may be a critical step for the restoration of the proper balance between pro and antifibrotic signaling pathways [10,11] in the kidney and other organs
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