淫羊藿苷对急性肾损伤向慢性肾脏病转化小鼠模型的预防性保护作用

doi:10.3969/j.issn.1674-8115.2023.01.002

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (1): 8-19.doi: 10.3969/j.issn.1674-8115.2023.01.002

淫羊藿苷对急性肾损伤向慢性肾脏病转化小鼠模型的预防性保护作用

谢林¹^,²(), 程烨²(), 郑琦敏¹, 张熙², 付莉莉³, 陈敏², 王怡², 梅长林³, 谢静远¹, 顾向晨¹^,²()

^1.上海交通大学医学院附属瑞金医院肾脏科，上海 200025
^2.上海中医药大学附属岳阳中西医结合医院肾脏科，上海 200437
^3.海军军医大学第二附属医院（上海长征医院）肾脏科，上海 200003

收稿日期:2022-04-29 接受日期:2022-12-16 出版日期:2023-01-28 发布日期:2023-01-28
通讯作者: 顾向晨，电子信箱：gettygugu@126.com。
作者简介:谢林（1994—），女，博士生；电子信箱：18516260652@163.com
程烨（1987—），女，主治医师，博士；电子信箱：hellochengye@163.com。第一联系人：（谢林、程烨并列第一作者）
基金资助:
国家自然科学基金面上项目(81774106);上海市浦江人才计划(18PJD049);上海交通大学医学院“中西医结合研究平台”(2022zxy003);上海中医药大学附属岳阳中西医结合医院院级基金(2021yyjm01)

Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model

XIE Lin¹^,²(), CHENG Ye²(), ZHENG Qimin¹, ZHANG Xi², FU Lili³, CHEN Min², WANG Yi², MEI Changlin³, XIE Jingyuan¹, GU Xiangchen¹^,²()

^1.Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
^2.Department of Nephrology, Yueyang Hospital of Integrated Traditional and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
^3.Department of Nephrology, The Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai 200003, China

Received:2022-04-29 Accepted:2022-12-16 Online:2023-01-28 Published:2023-01-28
Contact: GU Xiangchen, E-mail: gettygugu@126.com.
Supported by:
National Natural Science Foundation of China(81774106);Shanghai Pujiang Talent Program(18PJD049);Shanghai Jiao Tong University School of Medicine “Integrated Traditional Chinese and Western Medicine Research Platform”(2022zxy003);Program of Yueyang Hospital of Integrated Traditional and Western Medicine, Shanghai University of Traditional Chinese Medicine(2021yyjm01)

摘要/Abstract

摘要：

目的·探究淫羊藿苷在急性肾损伤（acute kidney disease，AKI）向慢性肾脏病（chronic kidney disease，CKD）转化中的作用并探讨其可能的机制。方法·C57BL/6小鼠腹腔注射马兜铃酸2周，制作AKI向CKD转化模型，并于造模前1周或马兜铃酸注射2周结束时持续灌胃给予淫羊藿苷5周或2周。监测小鼠肾功能和肾脏病理损伤，并用透射电子显微镜观察肾小管上皮细胞线粒体结构，采用荧光定量PCR（qPCR）及免疫组织化学染色法检测脂肪酸氧化代谢通路、纤维化及炎症指标等。采用Transwell细胞小室共培养大鼠肾脏成纤维细胞株和大鼠肾小管上皮细胞株，模拟2种细胞之间的相互作用。先提前1 h在肾小管上皮细胞培养液中加入淫羊藿苷，再加入马兜铃酸干预24 h；去除药物干预后，将肾小管上皮细胞与成纤维细胞共培养24 h。qPCR或Western blotting检测肾脏上皮细胞过氧化物酶体增殖物激活受体α（peroxisome proliferator activated receptor α，Ppara）、促纤维化因子、炎症因子、活化胱天蛋白酶（cleaved caspase-3），以及肾脏成纤维细胞细胞外基质相关基因mRNA或蛋白表达的变化。用Ppara-siRNA转染肾小管上皮细胞，观察淫羊藿苷提前于马兜铃酸干预后PPARα下游线粒体脂肪酸氧化代谢相关指标以及cleaved caspase-3的表达变化。结果·马兜铃酸注射2周结束时和注射结束后2周（造模4周），仅注射马兜铃酸的小鼠血清肌酐及尿素氮水平较对照组均显著升高，肾脏炎症细胞大量浸润，肾小管损伤严重；而提前给予淫羊藿苷干预的小鼠较马兜铃酸组肾功能明显改善，肾脏病理损伤减轻。造模4周时马兜铃酸组肾小管上皮细胞线粒体结构损伤严重，脂肪酸氧化代谢通路相关基因mRNA水平较对照组显著降低，伴巨噬细胞浸润及肾纤维化，提前给予淫羊藿苷干预后上述损伤或指标均明显缓解。在马兜铃酸注射2周结束时给予淫羊藿苷的小鼠血清肌酐和尿素氮水平、肾脏病理损伤、纤维化指标均与马兜铃酸组无明显差异。体外实验中，马兜铃酸可抑制肾小管上皮细胞Ppara mRNA表达，促进cleaved caspase-3、炎症因子及促纤维化因子表达升高，并上调共培养的肾脏成纤维细胞细胞外基质相关基因的表达，而淫羊藿苷提前干预对上述变化有明显的纠正作用。用siRNA敲低肾小管上皮细胞的Ppara后，淫羊藿苷对马兜铃酸抑制脂肪酸氧化代谢及促进细胞凋亡的预防保护作用减弱。结论·淫羊藿苷能预防马兜铃酸诱导的小鼠AKI向CKD转化；它可能是通过改善肾小管上皮细胞线粒体脂肪酸氧化代谢通路（尤其是PPARα）发挥作用。

关键词: 淫羊藿苷, 急性肾损伤, 慢性肾脏病, 线粒体, 脂肪酸氧化, 肾小管上皮细胞

Abstract:

Objective ·To investigate the effect of icariin on the transition from acute kidney disease (AKI) to chronic kidney disease (CKD) in mice and the possible mechanism. Methods ·C57BL/6 mice were intraperitoneally injected with aristolochic acid for 2 weeks to mimic AKI to CKD transition. Icariin was intragastrically administered for 2 or 5 weeks at the end of 2 weeks of aristolochic acid injection or 1 week before modeling. The renal function and pathological injury of the mice were monitored. The mitochondrial structure of renal tubular epithelial cells was observed by transmission electron microscopy. The indexes related to fatty acid oxidative metabolic pathway, fibrosis, and inflammation were detected by quantitative PCR (qPCR) and immunohistochemical staining. The rat renal fibroblast cell line and the rat renal tubular epithelial cell lines were co-cultured in Transwell cell chambers to simulate the interaction between the two types of cells. The renal tubular epithelial cells were pretreated with icariin for 1 h, and then treated with aristolochic acid for 24 h. After removing the two drugs, the renal tubular epithelial cells and the fibroblasts were co-cultured for 24 h. The mRNA or protein expression levels of peroxisome proliferator-activated receptor α (Ppara), pro-fibrotic factors, inflammatory factors, activated caspase-3 (cleaved caspase-3), and extracellular matrix-associated genes in renal fibroblasts were detected by qPCR or Western blotting. The renal tubular epithelial cells were transfected with Ppara-siRNA to observe the expression changes of cleaved caspase-3 and the related indicators of mitochondrial fatty acid oxidative metabolism in the downstream of PPARα after icariin intervention prior to aristolochic acid. Results ·Compared with the control group, the serum creatinine and urea nitrogen levels of the mice injected with aristolochic acid only were significantly higher, with a large number of inflammatory cells infiltrating into the kidney and serious renal tubular injury at the end of 2 weeks of aristolochic acid injection and 2 weeks after the last injection (4 weeks). The renal function was significantly improved, and the pathological damage was attenuated in the mice pretreated with icariin. After 4 weeks of modeling, the mitochondrial structure of renal tubular epithelial cells was seriously damaged in the aristolochic acid group, and the mRNA levels of fatty acid oxidative metabolic pathway-related genes were significantly downregulated, compared to the control group, accompanied by macrophage infiltration and renal fibrosis. Icariin pretreatment attenuated these damages generated by aristolochic acid. The serum creatinine and urea nitrogen levels, renal pathological injury, and fibrotic markers of the mice treated with icariin at the end of 2 weeks of aristolochic acid injection showed no difference from the aristolochic acid group. In the in vitro experiments, aristolochic acid treatment suppressed Ppara mRNA expression and elevated cleaved caspase-3, inflammatory factors, and pro-fibrotic factors in renal tubular epithelial cells. It also upregulated the expression of extracellular matrix-related genes in co-cultured renal fibroblasts. In contrast, icariin pretreatment abrogated the changes caused by aristolochic acid. The knockdown of Ppara by siRNA in renal tubular epithelial cells removed the preventive effects of icariin on aristolochic acid inhibiting fatty acid oxidative metabolism and promoting cell apoptosis. Conclusion ·Icariin prevents AKI to CKD transition induced by aristolochic acid in mice. It may play its protective role by improving the mitochondrial fatty acid oxidative metabolic pathway, especially through PPARα, in renal tubular epithelial cells.

Key words: icariin, acute kidney injury (AKI), chronic kidney disease (CKD), mitochondria, fatty acid oxidation, renal tubule epithelial cell

中图分类号:

R286

谢林, 程烨, 郑琦敏, 张熙, 付莉莉, 陈敏, 王怡, 梅长林, 谢静远, 顾向晨. 淫羊藿苷对急性肾损伤向慢性肾脏病转化小鼠模型的预防性保护作用[J]. 上海交通大学学报（医学版）, 2023, 43(1): 8-19.

XIE Lin, CHENG Ye, ZHENG Qimin, ZHANG Xi, FU Lili, CHEN Min, WANG Yi, MEI Changlin, XIE Jingyuan, GU Xiangchen. Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 8-19.

图/表 10

表1 实时荧光定量PCR引物序列

Tab 1 Primer sequences for real-time qPCR

Gene	Forward （5′→3′）	Reward （5′→3′）
Fn （mouse）	ATGGTACAGCTGATCCTGCC	GCCCTGGTTTGTACCTGCTA
Acta2 （mouse）	GGAACCCTGAGACGCTGCT	CATTCCAACCATTACTCCC
Col1a1 （mouse）	CCCAGCCGCAAAGAGTCTAC	AGCATACCTCGGGTTTCCAC
Tgfb1 （mouse）	GGGAAGCAGTGCCCGAACCC	TGGGGGTCAGCAGCCGGTTA
Hprt （mouse）	TATGCCGAGGATTTGGAAAA	TCCCATCTCCTTCATGACATC
Cpt1a （mouse）	CTTCCCATTTGACACCTTTG	ATACGTGAGGCAGAACTTGC
Col3a1 （mouse）	ACAGCTGGTGAACCTGG	ACCAGGAGATCCATCTCGAC
Vimentin （mouse）	GGATCAGCTCACCAACGACA	GGTCAAGACGTGCCAGAGAA
Cpt2 （mouse）	CCCAGGCTGCCTATCCCT	TCCTTCCCAATGCCGTTC
Ppara （mouse）	AGAGCCCCATCTGTCCTCTC	ACTGGTAGTCTGCAAAACCAAA
Acox2 （mouse）	GAGGGTGAGAATACGGT	GGTCTTGGTGTGGCGAG
Ppara （rat）	AACATCGAGTGTCGAATATGTGG	CCGAATAGTTCGCCGAAAGAA
Tnfa （rat）	ATGGGCTCCCTCTCATCAGT	GCTTGGTGGTTTGCTACGAC
Fn （rat）	AGAGGGGAGTGGAAGTGTGA	GTTGTAGGTGAACGGGAGAA
Tgfb1 （rat）	CTAATGGTGGACCGCAACAAC	CACTGCTTCCCGAATGTCTGA
Ctgf （rat）	AACCGTGTGTCATTGTCAT	CACCTTAGTGTGCGTTCTG
Cpt1a （rat）	ATGGAGGTTGTCTACGA	CAGGGGTTTACTTTTTA
Cpt2 （rat）	CAGCTGACCAAAGAAGCAGC	GTTCAGAGTGCTGGTGGACA
Col1a1 （rat）	CTGACGCATGGCCAAGAAGA	TTGGGTCCCTCGACTCCTAT
β-actin （rat）	GTAAAGACCTCTATGCCAACA	GGACTCATCGTACTCCTGCT

图1 马兜铃酸诱导的AKI-CKD小鼠模型的肾功能损伤以及淫羊藿苷的预防作用Note： A. The grouping diagram of the AKI-CKD mice model induced by AA1 and intervened by ICA. B. Blood urea nitrogen (BUN) after 2 weeks or 4 weeks. C. Serum creatinine (Scr) after 2 weeks or 4 weeks. ip—intraperitoneal injection. ①P=0.000, ②P=0.001, ③P=0.003, ④P=0.007, ⑤P=0.006.

Fig 1 Renal function injury in the AA1-induced AKI-CKD murine model and preventive effect of ICA

图2 AKI-CKD小鼠模型急性期肾脏的病理损伤以及淫羊藿苷的预防效果Note： A. Representative images of H-E, PAS and Masson staining kidney sections of AKI-CKD model after 2 weeks (×200). B. Renal tubular injury scores of the three groups after 2 weeks. C. Quantification of Masson trichrome staining after 2 weeks. Scale bar=100 μm. ①P=0.000.

Fig 2 Pathological changes of kidney in the AKI-CKD murine model at acute stage and preventive effect of ICA

图3 AKI-CKD小鼠模型重塑期肾脏的病理损伤以及淫羊藿苷的预防效果Note： A. Representative images of H-E, PAS and Masson staining kidney sections of AKI-CKD model after 4 weeks (×200). B. Renal tubular injury scores of the three groups after 4 weeks. C. Quantification of Masson trichrome staining after 4 weeks. Scale bar=100 μm. ①P=0.000.

Fig 3 Pathological changes of kidney in the AKI-CKD murine model at remodeling stage and preventive effect of ICA

图4 AKI-CKD小鼠模型重塑期肾小管线粒体结构损伤与相关mRNA的表达水平以及淫羊藿苷的预防效果Note： A. Representative electron microscopic images of mitochondria in renal tubular epithelial cells after 4 weeks (above ×2 500, scale bar=10 μm; below ×25 000, scale bar=500 nm). B?E. Relative mRNA expression levels of Ppara (B), Acox2 (C), Cpt1a (D) and Cpt2 (E) in renal tissues after 4 weeks. F. Representative images of kidney sections with immunohistochemical staining PPARα after 4 weeks (×200). G. Quantification of PPARα-positive areas in kidney sections after 4 weeks (scale bar=100 μm). ①P=0.001, ②P=0.000, ③P=0.002, ④P=0.007.

Fig 4 Mitochondrial structural damage and expression levels of related mRNAs in the AKI-CKD murine model at remodeling stage and preventive effect of ICA

图5 AKI-CKD小鼠模型重塑期的肾纤维化以及淫羊藿苷的预防作用Note： A. Representative images of kidney sections with immunohistochemical staining of α-SMA and collagen Ⅰ after 4 weeks (×200). B. Quantification of α-SMA-positive areas in kidney sections after 4 weeks. C. Quantification of collagen Ⅰ-positive areas in kidney sections after 4 weeks. D?F. Relative mRNA expression levels of Tgfb1 (D), Fn (E) and Col1a1 (F) in renal tissues after 4 weeks. Scale bar=50 μm. ①P=0.000, ②P=0.044, ③P=0.008, ④P=0.014, ⑤P=0.007, ⑥P=0.001, ⑦P=0.003.

Fig 5 Renal fibrosis in the AKI-CKD murine model at remodeling stage and preventive effect of ICA

图6 AKI-CKD小鼠模型重塑期肾脏巨噬细胞浸润及淫羊藿苷的预防作用Note： A. Representative images of kidney sections with immunohistochemical staining of F4/80 after 4 weeks. B. Quantification of F4/80 positive areas in kidney sections after 4 weeks. Scale bar=50 μm. ①P=0.000.

Fig 6 Renal macrophage infiltration in the AKI-CKD murine model at remodeling stage and preventive effect of ICA

图7 AKI-CKD小鼠模型急性期结束给予淫羊藿苷对小鼠肾脏的影响Note： A. The grouping diagram of the AKI-CKD mice model induced by AA1 and intervened by ICA. B. BUN after 4 weeks. C. Scr after 4 weeks. D. Renal tubular injury scores of the three groups after 4 weeks. E. Quantification of Masson trichrome staining after 4 weeks. F?J. Relative mRNA expression levels of Col1a1 (F), Col3a1 (G), Fn (H), vimentin (I) and Tgfb1 (J)in renal tissues after 4 weeks.

Fig 7 Effect of ICA on kidney of the AKI-CKD murine model at the end of acute phase

图8 淫羊藿苷通过保护肾小管上皮细胞抑制肾成纤维细胞活化Note： A?D. Relative mRNA expression levels of Ppara (A), Tnfa (B), Tgfb1 (C) and Ctgf (D) in renal tubular epithelial cells. E.Western blotting analysis of cleaved caspase-3 in renal tubular epithelial cells. F/G. Relative mRNA expression levels of Fn (F) and Col1a1 (G) in renal fibroblasts. H. Western blotting analysis of α-SMA in renal fibroblasts. Each experiment was repeated three times. n=3 in each group. ①P=0.009, ②P=0.002, ③P=0.006, ④P=0.034, ⑤P=0.017, ⑥P=0.000, ⑦P=0.005, ⑧P=0.029, ⑨P=0.010, ⑩P=0.020.

Fig 8 ICA inhibiting renal fibroblast activation through protecting renal tubular epithelial cells

图9 敲低 Ppara 后淫羊藿苷对肾小管上皮细胞脂肪酸氧化代谢相关基因及凋亡蛋白表达水平的影响Note： A. Western blotting analysis of PPARα protein expression in epithelial cells after siRNAs intervention. B. Relative mRNA expression level of Ppara in epithelial cells after siRNA3 intervention. C?E. Relative mRNA expression levels of Ppara (C), Cpt1a (D)and Cpt2 (E) in epithelial cells with NC-siRNA or siRNA3 intervention. F. Western blotting analysis of cleaved caspase-3 protein expression in epithelial cells with NC-siRNA or siRNA3 intervention. Each experiment was repeated three times. n=3. ①P=0.027, ②P=0.020, ③P=0.037, ④P=0.060, ⑤P=0.026, ⑥P=0.038, ⑦P=0.046, ⑧P=0.045.

Fig 9 Effect of ICA on expression levels of fatty acid oxidative metabolism-related mRNAs and the apoptotic protein in renal tubular epithelial cells after knocking down Ppara

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淫羊藿苷对急性肾损伤向慢性肾脏病转化小鼠模型的预防性保护作用

Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model

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