Investigating Antithyroid Effects of Propylthiouracil on the Ischemia and Reperfusion Injury in Rat' Kidney and Determining the Role of Nitric Oxide in Mediating this Effect.

Abstract

Background:Renal ischemia/reperfusion injury (IRI) is a major problem in renal transplantation, which occurs during the process of organ retrieval and storage, and is closely associated with acute rejection episodes and late allograft failure. Recent studies have revealed a new phenomenon called “chemical preconditioning” that can induce tolerance against the ischemic stress via a variety of proposed pathways especially nitric oxide (NO) system. Propylthiouracil (PTU) is suggested to modulate the intracellular NO signaling.Objectives:In this study, we investigated the preconditioning properties of chronic pretreatment with PTU in preventing renal IRI. In addition, we evaluated the involvement of NO pathway.Materials and Methods:Sixty adult male Wistar rats were allocated into six groups. All groups underwent right nephrectomy 15 days before intervention. In groups 1 (Chronic PTU + L-NG-nitro arginine methyl ester [L-NAME]) and 2 (Chronic PTU) oral PTU (500 mg/L in water) treatment was started 15 days before right nephrectomy to achieve the therapeutic plasma level of PTU. Fourteen days after nephrectomy, animals received either L-NAME (10 mg/kg) or its vehicle and renal IRI was induced 45 minutes later. Groups 3 and 4 (Control) received respectively L-NAME (10 mg/kg) and its vehicle 45 minutes before IRI. The last two groups were normal sham operated rats and PTU + sham. Rats were killed 24 hours after IRI. The blood samples were collected and assessed for serum blood urea nitrogen (BUN) and creatinine (Cr) level, and tissue samples were fixed in formalin for histopathologic scoring of tubular damage (H-score).Results:The mean BUN, Cr, and H-score of control group were 176.66 ± 12.24 mmol/L, 4.45 ± 0.44 μmol/L, and 83.5% ± 3.5%, respectively. Chronic pretreatment with PTU significantly improved BUN (40.4 ± 6.1 mmol/L), Cr (0.96 ± 0.068 μmol/L), and H-score (7.83% ± 4.02%) in IRI animals in comparison to those that were not treated with chronic PTU (P < 0.001) and L-NAME; however, it did not completely reversed the chronic PTU-induced protection (BUN, 93.33 ± 12.22 mmol/L; Cr, 2.7 ± 1.15 μmol/L, and H-score, 24.83% ± 3.5%). There was no significant difference between rats that were treated with L-NAME alone (group 5) and the control group.Conclusions:Our study demonstrates that preconditioning of kidney with chronic PTU administration protects renal tissue against IRI and this phenomenon was mediated through NO system. The results suggest a potential indication for using PTU to protect the kidney before transplantations and to reduce the risk of tissue rejection afterwards.