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

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