Elafibranor Inhibits Chronic Kidney Disease Progression in NASH Mice

Biomed Res Int. 2019 Jun 19;2019:6740616. doi: 10.1155/2019/6740616. eCollection 2019.

Abstract

Identification of new pharmacological approaches to inhibit the excessive fat intake-induced steatohepatitis and chronic kidney disease (CKD) is important. High-fat diet (HFD)-induced steatohepatitis and CKD share common pathogenesis involving peroxisome proliferator-activated receptor (PPAR)-α and -δ. Elafibranor, a dual PPARα/δ agonist, can ameliorate the HFD-induced steatohepatitis. Nonetheless, the effects of HFD-induced CKD had not yet explored. This study investigated the effects of elafibranor (elaf) on the progression of HFD-induced CKD in mice. In vivo and in vitro renal effects were evaluated in HFD-elaf mice receiving 12 weeks of elafibranor (from 13th to 24th week of HFD feeding) treatment. In elafibranor-treated HFD mice, increased insulin sensitivity, reduced obesity and body fat mass, decreased severity of steatohepatitis, increased renal expression of PPARα, PPARδ, SIRT1, and autophagy (Beclin-1 and LC3-II) as well as glomerular/renal tubular barrier markers [synaptopodin (podocyte marker), zona occludin-1, and cubulin], reduced renal oxidative stress and caspase-3, and less urinary 8-isoprostanes excretion were observed. Aforementioned benefits of elafibranor were associated with low renal tubular injury and tubulointerstitial fibrosis scores, less albuminuria, low urinary albumin-to-creatinine ratio, and preserved glomerular filtration rate. Acute incubation of podocytes and HK-2 cells with elafibranor or recombinant SIRT1 reversed the HFD-sera-induced oxidative stress, autophagy dysfunction, cell apoptosis, barrier marker loss, albumin endocytosis, and reuptake reduction. Besides hepatoprotective and metabolic beneficial effects, current study showed that elafibranor inhibited the progression of HFD-induced CKD through activation of renal PPARα, PPARδ, SIRT1, autophagy, reduction of oxidative stress, and apoptosis in mice with steatohepatitis.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Beclin-1 / genetics
  • Chalcones / pharmacology*
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Kidney / drug effects
  • Kidney / pathology
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Oxidative Stress / drug effects
  • PPAR alpha / genetics*
  • PPAR delta / genetics*
  • Podocytes / drug effects
  • Propionates / pharmacology*
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / pathology
  • Sirtuin 1 / genetics*

Substances

  • 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid
  • Beclin-1
  • Chalcones
  • Enzyme Inhibitors
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • PPAR alpha
  • PPAR delta
  • Ppara protein, mouse
  • Propionates
  • Sirt1 protein, mouse
  • Sirtuin 1