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Abstract: TH-PO890

Attenuated Lymphatic Proliferation Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Kim, Yaeni, Incheon St. Mary's Hosp, Catholic Univ of Korea, Incheon, SEoul, Korea (the Republic of)
  • Lim, Ji Hee, The Catholic University of Korea, SEOUL, Korea (the Republic of)
  • Kim, Min Young, The Catholic University of Korea, SEOUL, Korea (the Republic of)
  • Kim, Eun Nim, The Catholic University of Korea, SEOUL, Korea (the Republic of)
  • Hwang, Seon Deok, inha university, Incheon, Korea (the Republic of)
  • Choi, Bumsoon, Division of Nephrology, Department of Internal Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea, SEOUL, Korea (the Republic of)

Lymphangiogenesis occurs in response to renal injury in renal proximal tubular epithelial cells (PTECs) and infiltrating macrophages 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 lymphangiogenesis.


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.


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 RAW 267 cells, fenofibrate prevented palmitate- and high glucose-induced expression of VEGF-C, VEGFR-3, and LYVE-1 via activation of PPARa-AMPK-pACC signaling and enhanced expression of M1 phenotype macrophage.


A causal relationship between lipotoxicity and lymphatic proliferation with a cellular link to macrophage activation can be speculated; pro-inflammatory M1 type macrophages may be primarily involved in the development of intrarenal lymphangiogenesis through stimulation of VEGF-C and by its transdifferentiation into lymphatic endothelial cells.