Abstract: FR-PO607

Attenuating Lymphatic Proliferation by Fenofibrate Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Kim, Yaeni, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Lim, Ji Hee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Min Young, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Choi, Bumsoon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Hwang, Seon Deok, Inha University College of Medicine, Incheon, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

In diabetic nephropathy, the proliferation of lymphatic vessels correlates with the extent of intrarenal inflammatory cell infiltration and tubulointerstitial fibrosis. Peroxisome proliferative-activated receptor (PPAR)α plays an important role against lipotoxicity under the control of AMP-activated protein kinase (AMPK).

Methods

We evaluated whether fenofibrate, a PPARα agonist, has a renoprotective effect by ameliorating lipotoxicityassociated with lymphangiogenesis.

Results

In male C57BLKS/J db/db mice, fenofibrate ameliorated albuminuria and mesangialand tubular fibrosis and inflammation. Fenofibrate inhibited the accumulation of intra-renal free fatty acid and triglycerides, which was associated with increase in the expression of PPARα, phosphorylation of AMPK, activation of PPARγ co-activator 1α-phosphorylated acetyl-CoA carboxylase, and suppression of sterol regulatory element-binding protein 1 (SREBP-1) and carbohydrate regulatory element-binding protein 1 (ChREBP). Fenofibrate significantly 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 renal apoptosis and oxidative stress. In high-fat diet-fed spontaneously hypertensive rats (SHRs), fenofibrate also attenuated renal lymphatic proliferation and lipotoxicity-induced oxidative stress and apoptosis. In cultured HK2 cells, fenofibrate prevented palmitate- and high glucose-induced expression of VEGF-C, VEGFR-3, and LYVE-1 via activation of PPARα-AMPK-pACC signaling and suppression of SREBP-1 and ChREBP.

Conclusion

These results suggested that fenofibrate prevents diabetic nephropathy in db/db mice and high-fat diet-induced renal injury in SHRs by attenuating lymphatic proliferation,inflammation ,andoxidative stress through activation of PPARα-AMPK pathway, especially in renal proximal tubule cells.