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

Sun Ryoung Choi, Ji Hee Lim, Min Young Kim, Eun Nim Kim, Yaeni Kim, Beom Soon Choi, Yong Soo Kim, Hye Won Kim, Kyung Min Lim, Min Jeong Kim, Cheol Whee Park

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Background: 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. Methods: AdipoRon (30 mg/kg) was mixed into the standard chow diet and provided to db/db mice (db + AdipoRon, n = 8) and age-matched male db/m mice (dm + AdipoRon, n = 8) from 17 weeks of age for 4 weeks. Control db/db (db cont, n = 8) and db/m mice (dm cont, n = 8) were fed a normal diet of mouse chow. Results: AdipoRon-fed db/db 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 db/db mice with AdipoRon administration. Consistent up-regulation of phospho-Thr 172 AMP-dependent kinase (AMPK), peroxisome proliferative-activated receptor α (PPARα), phospho-Thr 473 Akt, phospho-Ser 79 Acetyl-CoA carboxylase (ACC), and phospho-Ser 1177 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)348-360
Number of pages13
JournalMetabolism: Clinical and Experimental
Volume85
DOIs
StatePublished - Aug 2018

Bibliographical note

Funding Information:
This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (JHL; 2015R1D1A1A01056984 , HWK; 2016R1A2B2015878 , CWP; 2016R1A2B2015980 ) and the Seoul St. Mary's Hospital R&D Project, The Catholic University of Korea (CWP; 52015B000100004 ).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • Adiponectin
  • Ceramide
  • Glomerular endothelial cell
  • Lipotoxicity
  • Podocyte diabetic nephropathy

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