关键词: 肾缺血再灌注损伤, 5羟色胺, 5羟色胺2A受体, 活性氧

Abstract: Ｏｂｊｅｃｔｉｖｅ：To investigate the relationship between renal ischemiareperfusion injury (RIRI) and 5hydroxytryptamine (5HT) degradation and evaluate effect of inhibiting 5HT synthesis and 5HT2A receptor (5HT2AR) on RIRI.
Ｍｅｔｈｏｄｏｌｏｇｙ：In male Wistar rats, the right kidney was removed and the left kidney was ischemia for 45 min, and then the blood supply was restored for 24 h to induce RIRI. The rats were randomly divided into the sham group; the RIRI model group; pretreated groups, which were treated with 5HT2AR antagonist sarpogrelate hydrochloride (SH), aromatic amino acid decarboxylase (AADC) inhibitor carbidopa (CDP), and SH and CDP cotreated preventive administration (pSC); and therapeutic administration (tSC) groups (SH∶CDP=2∶1). Each drugtreated group was administered the same dose by gavage. After 24 h of reperfusion, the blood and kidneys were collected. Serum creatinine (SCr) and blood urea nitrogen (BUN), and levels of malondialdehyde (MDA), total superoxide dismutas (TSOD), tumor necrosis factorα (TNFα), interleukin6 (IL6), 5HT and reactive oxygen species (ROS) in renal tissue were measured. Renal injuries were evaluated by HE staining. The expression and localization of Tryptophan hydroxylase (Tph1), AADC, 5HT2AR and monoamin oxidaseA (MAOA) in renal tissue were detected by Western blotting and immunohistochemistry, and the expression of Bax, Bcl2, Caspase3 and Caspase9 were detected by Western blotting. Apoptosis was detected by TUNEL staining.
Ｒｅｓｕｌｔｓ：Compared with the sham group, the expression of Tph1, AADC, 5HT2AR and MAOA were significantly increased in renal tissue from the RIRI model group (P<005). Furthermore, the high expression regions were in the proximal renal tubular epithelial cells, overlapping with the regions of kidney lesions. Compared with the model group, the expression of Tph1, AADC and MAOA were significantly prevented in SH, pSC and tSC groups (P<005); however, the expression of 5HT2AR was not suppressed in all drugtreated groups (P>005). In the CDP group, the upregulation of MAOA was also significantly suppressed (P<005). In each treatment group, renal tubular lesions, SCr and BUN, oxidative stress indexes MDA and TSOD were significantly ameliorated (P<005); 5HT and ROS levels were decreased (P<005); the concentration of inflammatory cytokines TNFα and IL6 were reduced; the expression of apoptosisassociated proteins Bax, Bcl2, Caspase3, and Caspase9 were ameliorated (P<005); and apoptosis was reduced, as detected by TUNEL. Notably, the efficacy of treatment in the pSC group was significantly better than that in the SH and CDP groups, showing a synergistic effect. Furthermore, the efficacy of pSC group was similar to that of tSC group.
Ｃｏｎｃｌｕｓｉｏｎ：The findings demonstrate that RIRI is probably induced by increased expression of 5HT synthetase, 5HT2AR, and MAOA in proximal renal tubular epithelial cells, leading to the increase of mitochondrial 5HT degradation and ROS production. These processes would result in oxidative stress, inflammation, and apoptosis. This study demonstrates that RIRI could be effectively treated by a combination of a 5HT2AR antagonist and a 5HT synthesis inhibitor.

Key words: renal ischemia-reperfusion injury, 5-hydroxytryptamine synthesis, 5-HT2A receptor, reactive oxygen species