title: GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy.
abstract: Chronic obstructive uropathy can cause irreversible kidney injury, atrophy and inflammation, which can ultimately lead to fibrosis. Epithelial-mesenchymal transition is a key trigger of fibrosis that is caused by up-regulation of TGF-β1 (transforming growth factor-β1) and ANGII (angiotensin II). H2S is an endogenously produced gasotransmitter with cytoprotective properties. We sought to elucidate the effects of the slow-releasing H2S donor GYY4137 on chronic ureteral obstruction and evaluate the potential mechanisms.
  
  
  
  Following unilateral ureteral obstruction male Lewis rats were given daily intraperitoneal administration of phosphate buffered saline vehicle (obstruction group) or phosphate buffered saline plus 200 μmol/kg GYY4137 (obstruction plus GYY4137 group) for 30 days. Urine and serum samples were collected to determine physiological parameters of renal function and injury. Kidneys were removed on postoperative day 30 to evaluate histopathology and protein expression. Epithelial-mesenchymal transition in LLC-PK1 pig kidney epithelial cells was induced with TGF-β1 and treated with GYY4137 to evaluate potential mechanisms via in vitro scratch wound assays.
  
  
  
  H2S treatment decreased serum creatinine and the urine protein-to-creatinine excretion ratio after unilateral ureteral obstruction. In addition, H2S mitigated cortical loss, inflammatory damage and tubulointerstitial fibrosis. Tissues showed decreased expression of epithelial-mesenchymal transition markers upon H2S treatment. Epithelial-mesenchymal transition progression in LLC-PK1 was alleviated upon in vitro administration of GYY4137.
  
  
  
  To our knowledge our findings demonstrate for the first time the protective effects of H2S in chronic obstructive uropathy. This may represent a potential therapeutic solution to ameliorate renal damage and improve the clinical outcomes of urinary obstruction.
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Shouzhe
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Fazil
authors.initials: F
authors.lastname: Visram
authors.affiliation: Department of Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Haig
authors.affiliation: Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Mok
authors.affiliation: Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Dameng
authors.initials: D
authors.lastname: Lian
authors.affiliation: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wood
authors.affiliation: Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Torregrossa
authors.affiliation: Medical School, University of Exeter, Exeter, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Whiteman
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Lobb
authors.affiliation: Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada; Department of Surgery, University of Western Ontario, London, Ontario, Canada; Multi-Organ Transplant Program, London Health Sciences Center, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada. Electronic address: alp.Sener@lhsc.on.ca.
authors.forename: Alp
authors.initials: A
authors.lastname: Sener
mesh_terms: D000818:Animals; D002908:Chronic Disease; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D009946:Organothiophosphorus Compounds / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D014517:Ureteral Obstruction / Q000150:complications*
chemical_list: C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D006862:Hydrogen Sulfide
keywords: angiotensin II; epithelial-mesenchymal transition; hydrogen sulfide; transforming growth factors; ureteral obstruction