Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Adiponectin is known to take part in the regulation of energy metabolism. AdipoRon, an orally-active synthetic adiponectin agonist, binds to both adiponectin receptors (AdipoR)1/R2 and ameliorates diabetic complications. Among the lipid metabolites, the ceramide subspecies of sphingolipids have been linked to features of lipotoxicity, including inflammation, cell death, and insulin resistance. We investigated the role of AdipoRon in the prevention and development of type 2 diabetic nephropathy.</P> <P><B>Methods</B></P> <P>AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to <I>db/db</I> mice (<I>db</I> + AdipoRon, <I>n</I> = 8) and age-matched male <I>db/m</I> mice (<I>dm</I> + AdipoRon, <I>n</I> = 8) from 17 weeks of age for 4 weeks. Control <I>db/db</I> (<I>db</I> cont, <I>n</I> = 8) and <I>db/m</I> mice (<I>dm</I> cont, <I>n</I> = 8) were fed a normal diet of mouse chow.</P> <P><B>Results</B></P> <P>AdipoRon-fed <I>db/db</I> mice showed a decreased amount of albuminuria and lipid accumulation in the kidney with no significant changes in serum adiponectin, glucose, and body weight. Restoring expression of adiponectin receptor-1 and -2 in the renal cortex was observed in <I>db/db</I> mice with AdipoRon administration. Consistent up-regulation of phospho-Thr<SUP>172</SUP> AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr<SUP>473</SUP> Akt, phospho-Ser<SUP>79</SUP>Acetyl-CoA carboxylase (ACC), and phospho-Ser<SUP>1177</SUP> endothelial NO synthase (eNOS), and down-regulation of protein phosphatase 2A (PP2A), sterol regulatory element-binding protein-1c (SREBP-1c), and inducible nitric oxide synthase (iNOS) were associated within the same group. AdipoRon lowered cellular ceramide levels by activation of acid ceramidase, which normalized ceramide to sphingosine-1 phosphate (S1P) ratio. In glomerular endothelial cells (GECs) and podocytes, AdipoRon treatment markedly decreased palmitate-induced lipotoxicity, which ultimately ameliorated oxidative stress and apoptosis.</P> <P><B>Conclusions</B></P> <P>AdipoRon may prevent lipotoxicity in the kidney particularly in both GECs and podocytes through an improvement in lipid metabolism, as shown by the ratio of ceramide to sphingosines, and further contribute to prevent deterioration of renal function, independent of the systemic effects of adiponectin. The reduction in oxidative stress and apoptosis by AdipoRon provides protection against renal damage, thereby ameliorating endothelial dysfunction in type 2 diabetic nephropathy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Superfluous ceramide via decrease in acid ceramidase activity causes lipotoxicity. </LI> <LI> Adiponectin and adiponectin receptors potentially increase ceramidase activity. </LI> <LI> AdipoRon ameliorated renal lipotoxicity by AdipoR1-AMPK and AdipoR2-PPARα pathway. </LI> <LI> AdipoRon is a promising tool for treatment of diabetic nephropathy in type 2 DM. </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>