GYY4137, a slow-releasing hydrogen sulfide donor, ameliorates renal damage associated with chronic obstructive uropathy.
The Journal of Urology
This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.
Reason for embargo
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.
This work was supported by a grant from the Lawson Health Research Foundation.