대한신장학회

논문분류	춘계학술대회 초록집
제목	Attenuated Lymphatic Proliferation Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity
저자	Yaeni Kim1, Ji Hee Kim2, Min Young Kim2, Eun Nim Kim2, Bum Soon Choi2, Yong-Soo Kim2, Seon Deok Hwang3, Cheol Whee Park2
출판정보	2018; 2018(1):
키워드	Fenofibrate \| Lipotoxicity \| Diabetic nephropathy \| Lymphangiogenesis
초록	Objectives: Lymphangiogenesis occurs in response to renal injury and is correlated with the degree of renal interstitial fibrosis. Diabetes and high-fat diet-induced renal lipotoxicity causes glomerular sclerosis and tubulointersitial fibrosis, but its possible involvement with regard to lymphangiogenesis has not been elucidated. Peroxisome proliferative-activated receptor (PPAR)a plays an important role against lipotoxicity under the control of AMP-activated protein kinase (AMPK). We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity-induced inflammation and lymphangiogenesis. Methods: Eight-week-old male C57BLKS/J db/db mice and spontaneously hypertensive rats (SHRs) were fed either a normal chow or a high-fat diet (HFD) and fenofibrate for 12 weeks and were evaluated for biochemical parameters and renal phenotypes. Results: In db/db mice, fenofibrate inhibited the accumulation of intra-renal lipids by increasing the expression of PPARa and phosphorylation of AMPK. It decreased lymphatic growth, as represented by decreases in the expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin, along with decreases in vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3). Consequently, fenofibrate reversed mesangial expansion, tubulointerstitial fibrosis and chemokine-induced inflammatory cell infiltration by improving apoptosis and oxidative stress. In HFD SHRs, fenofibrate attenuated renal lymphatic proliferation and inflammation by decreasing lipotoxicity-induced oxidative stress and apoptosis through PPARa-AMPK phosphorylation. In cultured HK2 cells and macrophages, fenofibrate prevented palmitate- and high glucose-induced expression of VEGF-C, VEGFR-3, and LYVE-1 via activation of PPARa-AMPK-pACC signaling. It is speculated that PTECs potential as a source of VEGF-C and macrophages’ lymphangiogenic capacity via its transdifferentiation into lymphatic endothelial cells may have been suppressed by fenofibrate treatment. Conclusions: Fenofibrate prevented lipid-induced renal damage in db/db mice and HFD SHRs by attenuating lymphatic proliferation through the activation of PPARa-AMPK pathway, especially in renal PTECs and macrophages.
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