Daily therapy with a slow-releasing H2S donor GYY4137 enables early functional recovery and ameliorates renal injury associated with urinary obstruction

Shouzhe Lin; Dameng Lian; Weihua Liu; Aaron Haig; Ian Lobb; Ahmed Hijazi; Hassan Razvi; Jeremy Burton; Matthew Whiteman; Alp Sener

doi:10.1016/j.niox.2018.03.002

Daily therapy with a slow-releasing H₂S donor GYY4137 enables early functional recovery and ameliorates renal injury associated with urinary obstruction

Nitric Oxide. 2018 Jun 1:76:16-28. doi: 10.1016/j.niox.2018.03.002. Epub 2018 Mar 6.

Authors

Shouzhe Lin¹, Dameng Lian², Weihua Liu³, Aaron Haig³, Ian Lobb⁴, Ahmed Hijazi⁵, Hassan Razvi⁶, Jeremy Burton⁷, Matthew Whiteman⁸, Alp Sener⁹

Affiliations

¹ Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
² Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
³ Department of Pathology, Western University, London, Ontario, Canada.
⁴ Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, London, Ontario, Canada.
⁵ Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
⁶ Department of Surgery, Western University, London, Ontario, Canada.
⁷ Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
⁸ University of Exeter Medical School, University of Exeter, Exeter, Devon, United Kingdom.
⁹ Department of Microbiology and Immunology, Western University, London, Ontario, Canada; Department of Surgery, Western University, 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.

PMID: 29522906
DOI: 10.1016/j.niox.2018.03.002

Abstract

Objectives: To assess the effects of slow-releasing H₂S donor GYY4137 on post-obstructive renal function and injury following unilateral ureteral obstruction (UUO) by using the UUO and reimplantation (UUO-R) model in rats and to elucidate potential mechanisms by using an in vitro model of epithelial-mesenchymal transition (EMT).

Methods: Male Lewis rats underwent UUO at the left ureterovesical junction. From post-operative day (POD) 1-13, rats received daily intraperitoneal (IP) injection of phosphate buffered saline (PBS, 1 mL) or GYY4137 (200 μmol/kg/day in 1 mL PBS, IP). On POD 14, the ureter was reimplanted back into the bladder, followed by a right nephrectomy. Urine and serum samples were collected to monitor renal function. On POD 30, the left kidney was removed and tissue sections were stained with H&E, TUNEL, CD68, CD206, myeloperoxidase, and Masson's trichrome to determine cortical thickness, apoptosis, inflammation, and fibrosis. In our in vitro model of EMT, NRK52E cells were treated with 10 ng/mL TGF-β1, 10 μM GYY4137 and/or 50 μM GYY4137. Western blot analysis was performed to determine the expression of E-cadherin, vimentin, Smad7 and TGF-β1 receptor II (TβRII).

Results: GYY4137 led to a moderate decrease in post-obstructive serum creatinine, cystatin C and FENa. We also observed a trend towards a decrease in post-obstructive proteinuria following GYY4137 treatment. Histologically, we observed a significant decrease in apoptosis, inflammation, and fibrosis. Furthermore, our in vitro studies demonstrate that in the presence of TGF-β1, GYY4137 significantly decreases vimentin and TβRII and significantly increases E-cadherin and Smad7.

Conclusions: H₂S may help to accelerate the recovery of renal function post-obstruction and attenuates renal injury associated with UUO. It is possible that H₂S mitigates fibrosis by regulating the TGF-β1-mediated EMT pathway. Taken together, our data suggest that H₂S may be a potential novel therapy for improving renal function and limiting renal injury associated with obstructive uropathy.

Keywords: Epithelial mesenchymal transition; Hydrogen sulfide; Renal function; Renal injury; Transforming growth factor beta 1; Unilateral ureteral obstruction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Kidney / drug effects*
Kidney / injuries*
Kidney / pathology
Kidney Diseases / drug therapy*
Kidney Diseases / etiology*
Male
Morpholines / pharmacology*
Organothiophosphorus Compounds / pharmacology*
Rats
Rats, Inbred Lew
Ureteral Obstruction / complications*
Ureteral Obstruction / pathology

Substances

GYY 4137
Morpholines
Organothiophosphorus Compounds

Grants and funding

MC_PC_16044/MRC_/Medical Research Council/United Kingdom