氢氧化镧灌胃对大鼠慢性肾功能衰竭高磷血症的治疗作用及其机制

Therapeutic effect and mechanism of lanthanum hydroxide administration on hyperphosphatemia in rats with chronic renal failure

目的观察氢氧化镧(LH)对大鼠慢性肾功能衰竭高磷血症的治疗作用,并探讨其作用机制。方法将30只Wistar大鼠按随机数字表分为5组各6只,对照组不制备慢性肾功能衰竭高磷血症模型,模型组、低剂量组、中剂量组、高剂量组制备慢性肾功能衰竭高磷血症模型,制模后低剂量组、中剂量组、高剂量组分别灌胃给予0.1、0.2、0.4 g/kg的LH,共8周;模型组和对照组不予处理。采用钙(Ca)、磷(PI)、肌酐(Scr)、尿素氮(BUN)试剂盒检测各组血清Ca、PI、Scr、BUN,苏木精—伊红(HE)、马松三色(Masson’s)染色法检测肾脏组织病理变化;另利用液相色谱质谱联用仪(LC-MS)检测对照组、模型组及低、中、高剂量组肾功能差异代谢物,并分析肾功能差异代谢物GO功能、KEGG富集。结果给药8周后,与模型组相比,给予LH各剂量组治疗后慢性肾功能衰竭高磷血症大鼠血清PI、Scr、BUN水平降低,肾损伤、肾小管囊性扩张、炎症细胞浸润得到改善,肾小管囊性扩张、炎症细胞浸润以及纤维化程度减轻,肾损伤得到延缓,且呈剂量依赖性(P均<0.05)。代偿性上调的肾功能差异代谢物分别是D-丙氨酰-D-丙氨酸、6-叔丁基磺酸、氨基二环二羧酸、1D-肌醇等;代偿性下调的肾功能差异代谢物分别是DL-瓜氨酸、2,3-前列腺素、鸟氨酸、2-磺氧基甲基、对羧基苯磺酰胺等。这些肾功能差异代谢物富集到的代谢通路有尿素循环、精氨酸和脯氨酸代谢、磷酸戊糖途径、赖氨酸降解、苹果酸-天冬氨酸循环、天冬氨酸代谢、丙氨酸代谢等。结论LH对大鼠慢性肾功能衰竭高磷血症有治疗作用,且高剂量LH最为显著,LH可能通过尿素循环、精氨酸代谢等途径来发挥治疗作用。

Objective To observe the therapeutic effect of lanthanum hydroxide(LH)on hyperphosphatemia in rats with chronic renal failure and explore its mechanism.Methods Thirty Wistar rats were randomly divided into five groups,with 6 rats in each group.No hyperphosphatemia model of chronic renal failure was prepared in the control group,and the hyperphosphatemia models were prepared in the model group,low-dose group,medium-dose group and high-dose group.After modeling,the rats in the low-dose group,medium-dose group,and high-dose group were given 0.1,0.2,and 0.4 g/kg LH by gavage,respectively,for a total of 8 weeks.The rats in the model group and control group were not treated.Calcium(Ca),phosphorus(PI),creatinine(Scr)and urea nitrogen(BUN)kits were used to detect serum Ca,PI,Scr and BUN,and hematoxylin-eosin(HE)and Masson's staining were used to detect the pathological changes of kidney tissues.In addition,liquid chromatography-mass spectrometry(LC-MS)was used to detect renal differential metabolites in the control group,model group,low-dose,medium-does and high-dose groups,and we analyzed the GO function and KEGG enrichment of renal differential metabolites.Results After 8 weeks of administration,compared with the model group,the serum PI,Scr and BUN levels of rats with chronic renal failure and hyperphosphatemia decreased in the LH groups after treatment,and renal injury,cystic dilatation of renal tubules and inflammatory cell infiltration were improved,and cystic dilatation of renal tubules,inflammatory cell infiltration and fibrosis degree,and renal injury were alleviated.They were in a dose-dependent manner(all P<0.05).The differential metabolites of renal function with compensatory up-regulation were D-alanyl-D-alanine,6-tert-butylsulfonic acid,aminodicyclodicarboxylic acid and 1D inositol.The differential metabolites of renal function with compensatory down-regulation were DL-citrulline,2,3-prostaglandin,ornithine,2-sulfoxymethyl,and p-carboxybenzene sulfonamide,etc.The metabolic pathways enriched by these metabolites in renal function differences included urea cycle,arginine and proline metabolism,pentose phosphate pathway,lysine degradation,malate-aspartic acid cycle,aspartic acid metabolism,and alanine metabolism,etc.Conclusions LH has a therapeutic effect on hyperphosphatemia of chronic renal failure rats,and high-dose LH is the most significant.LH may play a therapeutic role through urea cycle and arginine metabolism.