GYY4137, a slow-releasing hydrogen sulfide donor, ameliorates renal damage associated with chronic obstructive uropathy.
Lin, S; Visram, F; Liu, W; et al.Haig, A; Jiang, J; Mok, A; Lian, D; Wood, ME; Torregrossa, R; Whiteman, M; Lobb, I; Sener, A
Date: 10 May 2016
Journal
The Journal of Urology
Publisher
Elsevier
Publisher DOI
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Abstract
PURPOSE: Chronic obstructive uropathy can cause irreversible kidney injury, atrophy, and inflammation, which can ultimately lead to fibrosis. Epithelial-mesenchymal transition (EMT) is a key trigger of fibrosis and is caused by upregulation of transforming growth factor beta 1 (TGF-β1) and angiotensin II (ANGII). Hydrogen sulfide (H2S) ...
PURPOSE: Chronic obstructive uropathy can cause irreversible kidney injury, atrophy, and inflammation, which can ultimately lead to fibrosis. Epithelial-mesenchymal transition (EMT) is a key trigger of fibrosis and is caused by upregulation of transforming growth factor beta 1 (TGF-β1) and angiotensin II (ANGII). Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cytoprotective properties. The present study aims to elucidate the effects of the slow-releasing H2S donor GYY4137 on chronic ureteral obstruction and evaluate potential mechanisms. MATERIALS AND METHODS: Following unilateral ureteral obstruction (UUO), male Lewis rats were given daily intraperitoneal (IP) administration of phosphate buffered saline (PBS) vehicle (UUO group) or PBS+200μmol/kg GYY4137 (UUO+GYY4137 group) for 30 days. Urine and serum samples were collected to determine physiological parameters of renal function and injury. Kidneys were removed on post-operative day 30 for evaluation of histopathology and protein expression. EMT in pig kidney epithelial cells (LLC-PK1) was induced with TGF-β1 and treated with GYY4137 to evaluate potential mechanisms via in vitro scratch wound assays. RESULTS: H2S treatment decreased serum creatinine and urine protein/creatinine excretion ratio following UUO. In addition, H2S mitigated cortical loss, inflammatory damage, and tubulointerstitial fibrosis. Tissues exhibited decreased expression of EMT markers upon H2S treatment. EMT progression in LLC-PK1 was alleviated upon in vitro administration of GYY4137. CONCLUSIONS: Our findings demonstrate, for the first time, the protective effects of H2S in chronic obstructive uropathy and may represent a potential therapeutic solution to ameliorate renal damage and improve clinical outcomes of urinary obstruction.
Institute of Biomedical & Clinical Science
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