Attenuated Lymphatic Proliferation Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity
Attenuated Lymphatic Proliferation Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity
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DOI：
10.1038/s41598-018-38250-7
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发表时间：
2019-02-13
影响因子：
4.6
通讯作者：
Park, Cheol Whee
中科院分区：
文献类型：
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作者：
Kim, Yaeni;Hwang, Seun Deuk;Park, Cheol Whee
淋巴管生成反应于肾损伤，并与间质纤维化相关。糖尿病和高脂饮食（HFD）诱导的肾内脂毒性及其与淋巴管生成的关系尚未建立。我们使用PPARa激动剂非诺贝特来阐明脂毒性和淋巴管生成之间的联系。8周龄雄性C57 BLKS/J db/db小鼠和HFD自发性高血压大鼠（SHR）喂食非诺贝特12周。HK-2和RAW264.7细胞用于研究它们的淋巴管生成能力与脂毒性的关系。非诺贝特通过增加PPARa的表达和AMPK的磷酸化来改善肾内脂毒性。淋巴增殖减弱;淋巴管内皮透明质酸受体-1（LYVE-1）、podoplanin、血管内皮生长因子-C（VEGF-C）和血管内皮生长因子受体-3（VEGFR-3）的表达降低。与此同时，肾小管间质纤维化、细胞凋亡和炎性细胞浸润的程度减少。在HK 2细胞中，非诺贝特通过激活PPARa-AMPK-pACC信号转导减少棕榈酸和高糖诱导的淋巴标记物的过度表达。RAW264.7细胞中M1表型表达增强与淋巴管生长增加相关。可以推测脂毒性和淋巴增殖与巨噬细胞活化的细胞联系之间的因果关系;促炎性M1型巨噬细胞通过刺激VEGF-C及其转分化为淋巴管内皮细胞参与淋巴管生成的发展。
Lymphangiogenesis occurs in response to renal injury and is correlated with interstitial fibrosis. Diabetes-and high-fat diet (HFD)-induced intrarenal lipotoxicity and their relationships with lymphangiogenesis are not established. We used PPARa agonist, fenofibrate, to unravel the linkage between lipotoxicity and lymphangiogenesis. Eight-week-old male C57BLKS/J db/db mice and HFD Spontaneously hypertensive rats (SHRs) were fed fenofibrate for 12 weeks. HK-2 and RAW264.7 cells were used to investigate their lymphangiogenic capacity in relation to lipotoxicity. Fenofibrate improved intrarenal lipotoxicity by increasing expression of PPARa and phosphorylation of AMPK. Lymphatic proliferation was attenuated; expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, vascular endothelial growth factor-C (VEGF-C), and vascular endothelial growth factor receptor-3 (VEGFR-3) was decreased. In parallel, extent of tubulointerstitial fibrosis, apoptosis and inflammatory cell infiltration was reduced. In HK2 cells, palmitate-and high glucose-induced over expression of lymphatic makers was diminished by fenofibrate via activation of PPARa-AMPK-pACC signaling. Enhanced expression of M1 phenotype in RAW264.7 cells correlated with increased lymphatic growth. A causal relationship between lipotoxicity and lymphatic proliferation with a cellular link to macrophage activation can be speculated; pro-inflammatory M1 type macrophage is involved in the development of lymphangiogenesis through stimulation of VEGF-C and by its transdifferentiation into lymphatic endothelial cells.