The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

J Am Soc Nephrol. 2018 Apr;29(4):1108-1127. doi: 10.1681/ASN.2017060627. Epub 2018 Jan 12.

Abstract

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.

Keywords: AdipoRon; Lipotoxicity; diabetic nephropathy; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / physiology
  • Adiponectin / physiology*
  • Animals
  • Apoptosis / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / prevention & control
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Glucose / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Oxidative Stress / drug effects
  • PPAR alpha / physiology
  • Phosphorylation
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Podocytes / drug effects
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / physiology
  • Receptors, Adiponectin / agonists*
  • Receptors, Adiponectin / analysis*
  • Receptors, Adiponectin / physiology
  • Receptors, Leptin / deficiency

Substances

  • ADIPOR1 protein, human
  • ADIPOR2 protein, human
  • AdipoRon
  • Adiponectin
  • PPAR alpha
  • Piperidines
  • Receptors, Adiponectin
  • Receptors, Leptin
  • adiponectin receptor 1, mouse
  • adiponectin receptor 2, mouse
  • leptin receptor, mouse
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • AMP-Activated Protein Kinases
  • Glucose