目的 探索玄參水提物（SNAE）對腎陰虛水腫大鼠的治療作用及對體內(nèi)物質(zhì)與能量代謝的影響。方法 將48只雄性SD大鼠隨機(jī)分為對照組、陰虛組、陰虛恢復(fù)組、陰虛水腫模型組、SNAE（2.7 g·kg^-1）組和呋塞米（陽性藥，3.6 mg·kg^-1）組，每組8只。除對照組ig 0.9%氯化鈉溶液外，其余各組均ig給予甲狀腺素和利血平注射液混合物，連續(xù)10 d，制備大鼠腎陰虛模型；于第11天ip給予陰虛水腫模型組、SNAE組和呋塞米組氨基核苷嘌呤霉素（PAN）溶液，制備腎源性水腫模型，陰虛恢復(fù)組和對照組ip給予0.9%氯化鈉溶液；于12 d起ig給藥，每天1次。于取材的前1天禁食、不禁水12 h，陰虛組于第11天、其他組于第18天取材。取腎組織進(jìn)行蘇木素-伊紅（HE）染色后光鏡下觀察、透射電鏡下腎臟超微病理學(xué)觀察；全自動生化儀檢測血清肌酐（Scr）、尿素氮（BUN）、總蛋白（TP）、血漿白蛋白（ALB）以及尿液中尿蛋白（UP）水平，試劑盒法檢測血清睪酮（T）、雌二醇（E₂）、三碘甲狀腺原氨酸（T₃）、甲狀腺素（T₄）水平以及環(huán)磷酸腺苷（cAMP）/環(huán)磷酸鳥苷（cGMP）；應(yīng)用UPLC-Q-TOF-MS技術(shù)對各組大鼠尿液進(jìn)行分析，通過多變量統(tǒng)計(jì)分析篩選潛在生物標(biāo)志物，結(jié)合人類代謝組學(xué)數(shù)據(jù)庫（HMDB）和Metlin在線數(shù)據(jù)庫鑒定重要生物標(biāo)志物，并將鑒定到的生物標(biāo)志物導(dǎo)入京都基因與基因組百科全書數(shù)據(jù)庫（KEGG）推測其可能的代謝通路。結(jié)果 病理學(xué)結(jié)果顯示，與對照組、陰虛組、陰虛恢復(fù)組相比，陰虛水腫模型組腎臟病理損傷較明顯；與陰虛水腫組比較，SNAE、呋塞米對模型大鼠病理損傷程度有明顯改善作用；在藥效學(xué)指標(biāo)上，與陰虛水腫模型組比較，SNAE能顯著下調(diào)Scr、BUN、T₄水平（P<0.05），顯著上調(diào)T、E₂、cAMP/cGMP、TP、ALB水平（P<0.05、0.01）；代謝組學(xué)結(jié)果顯示，SNAE可改善各陰虛組大鼠代謝軌跡的偏離。通過對大鼠尿液代謝產(chǎn)物變化的預(yù)測，得到符合要求的生物標(biāo)志物共14個，包括檸檬酸、磷酸烯醇式丙酮酸、6-磷酸葡萄糖酸、尿酸、庚二酸、2-異丙基蘋果酸等；涉及15條相關(guān)代謝通路，關(guān)鍵代謝途徑主要富集于三羧酸（TCA）循環(huán)。結(jié)論 SNAE通過調(diào)節(jié)能量代謝相關(guān)通路發(fā)揮“滋陰、利水”等功效，從而對腎陰虛水腫發(fā)揮治療作用。

Objective Exploring the therapeutic effect of Scrophularia ningpoensis aqueous extract (SNAE) on edema caused by kidney yin deficiency in rats and its impact on substance and energy metabolism in the body. Methods Forty-eight male SD rats were randomly divided into control group, Yin deficiency group, Yin deficiency recovery group, Yin deficiency edema group, SNAE (2.7 g·kg^-1) group and furosemide (positive, 3.6 mg·kg^-1) group, with eight rats in each group. Except control group, which was given 0.9% sodium chloride solution by ig, the other groups were ig given the mixture of thyroxine and rexepin injection intragastric for 10 consecutive days to replicate the model of kidney-yin deficiency in rats. On the 11th day, the edema group, furosemide group and SNAE group were ip given puromycin aminonucleoside (PAN) solution to replicate the model of nephrogenic edema, and the Yin deficiency recovery group and the control group were given 0.9% sodium chloride solution via ip. Administer ig once a day starting from 12 days. On the day before sampling, fasting and uncontrollable hydration were performed for 12 hours. Administer ig once a day starting from 12 days. The Yin deficiency group was sampled on the 11th day, while the other groups were sampled on the 18th day. Taked kidney tissue for hematoxylin eosin (HE) staining and observed under light microscopy and transmission electron microscopy for renal ultrastructural pathology. The automatic biochemical analyzer detected serum creatinine (Scr), urea nitrogen (BUN), total protein (TP), plasma albumin (ALB), and urine protein (UP) levels. The kit method detected serum testosterone (T), estradiol (E₂), triiodothyronine (T₃), thyroxine (T₄) levels, as well as cyclic adenosine monophosphate (cAMP)/ cyclic guanosine monophosphate (cGMP) levels. Applied UPLC-Q-TOF-MS technology to analyze the urine of rats in each group, screen potential biomarkers through multivariate statistical analysis, and combined with the human metabolomics database (HMDB) to search and literature identification of important biomarkers. Imported the identified biomarkers into the Kyoto Encyclopedia of Genes and Genomes database (KEGG) to speculate their possible metabolic pathways. Results The pathological results showed that compared with the control group, Yin deficiency group, and Yin deficiency recovery group, the kidney pathological damage in the Yin deficiency edema model group was more significant. Compared with the Yin deficiency edema group, SNAE and furosemide had a significant improvement effect on the degree of pathological damage in model rats. In terms of pharmacodynamic indicators, compared with the Yin deficiency edema model group, SNAE significantly downregulated the levels of Scr, BUN, and T₄ (P< 0.05), and significantly upregulated the levels of T, E₂, cAMP/cGMP, TP, and ALB (P< 0.05, 0.01). Metabolomics results showed that SNAE can improve the deviation of metabolic trajectories in rats of various yin deficiency groups. By predicting changes in metabolic products in rat urine, a total of 14 biomarkers were obtained that meet the requirements, including citric acid, phosphoenolpyruvate, 6-phosphogluconic acid, uric acid, succinic acid, 2-isopropylmalic acid, etc. It involves 15 related metabolic pathways, with key metabolic pathways mainly enriched in the tricarboxylic acid (TCA) cycle. Conclusion SNAE exerts therapeutic effects on kidney yin deficiency and edema by regulating energy metabolism related pathways, such as nourishing yin and promoting diuresis.

國家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃（973計(jì)劃）資助項(xiàng)目（2013CB531804）；黑龍江中醫(yī)藥大學(xué)優(yōu)秀創(chuàng)新人才支持計(jì)劃資助（15041180088）