Atrasentan increased the expression of klotho by mediating miR-199b-5p and prevented renal tubular injury in diabetic nephropathy

Sci Rep. 2016 Jan 27;6:19979. doi: 10.1038/srep19979.

Abstract

Atrasentan is a promising therapy for treating diabetic nephropathy (DN). Here we evaluated whether atrasentan down-regulated the miR-199b-5p expression, thereby increasing klotho and preventing renal tubular injury in DN. One-hundred patients with type 2 diabetes mellitus (T2DM) and 40 healthy subjects were included. A DN mice model was established by an injection of streptozotocin (STZ). Human renal proximal tubular epithelial HK-2 cells were exposed to high glucose (20 mmol/L). Treated the mice and HK-2 cells with atrasentan, and we then investigated whether and how miR-199b-5p and Klotho were involved in preventing renal tubular injury in DN. In patients, the serum miR-199b-5p level increased and the klotho concentration decreased in accordance with elevated albuminuria. Atrasentan down-regulated miR-199b-5p and up-regulated klotho of the DN mice and HK-2 cells exposed to high glucose. High glucose promoted the binding of histone H3 to the miR-199b-5p promoter, and atrasentan canceled this effect. MiR-199b-5p targeted the 3' UTR of klotho. Overexpression of miR-199b-5p canceled the effects of atrasentan on klotho expression and apoptosis of renal tubular cells in both in vivo and in vitro. The increased serum klotho, mediated by miR-199b-5p, is a possible mechanism by which atrasentan prevents renal tubular injury in DN.

MeSH terms

  • 3' Untranslated Regions
  • Albuminuria
  • Animals
  • Antioxidants / metabolism
  • Atrasentan
  • Biomarkers
  • Cell Line
  • DNA Methylation
  • Diabetic Nephropathies / diagnosis
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology*
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation / drug effects*
  • Glucuronidase / genetics*
  • Humans
  • Kidney Function Tests
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism*
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Promoter Regions, Genetic
  • Pyrrolidines / pharmacology*
  • RNA Interference

Substances

  • 3' Untranslated Regions
  • Antioxidants
  • Biomarkers
  • MicroRNAs
  • Pyrrolidines
  • mirn199 microRNA, human
  • Glucuronidase
  • klotho protein
  • Atrasentan