Cited by 229Chronic Kidney Disease and DiabetesAdipokines, Inflammation, and Metabolic DiseasesRenal Diseases and Glomerulopathies

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

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Kim, Yaeni, Lim, Ji Hee, Kim, Min Young, Kim, Eun Nim, Yoon, Hye Eun, Shin, Seok Joon, Choi, Bum Soon, Kim, Yong-Soo +2 more·2018·Journal of the American Society of Nephrology

Abstract

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor– α (PPAR α ) 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 Ca 2+ /calmodulin-dependent protein kinase kinase– β (CaMKK β ) 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 CaMKK β , phosphorylated Ser 431 LKB1, phosphorylated Thr 172 AMPK, and PPAR α 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 Ca 2+ levels that activated a CaMKK β /phosphorylated Ser 431 LKB1/phosphorylated Thr 172 AMPK/PPAR α 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 Ca 2+ /LKB1-AMPK/PPAR α pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

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Crossref · 10.1681/asn.2017060627

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Authors
Kim, Y., Lim, J. H., Kim, M. Y., Kim, E. N., Yoon, H. E., Shin, S. J., Choi, B. S., Kim, Y.-S., Chang, Y. S., & Park, C. W.
Affiliations
  • The Catholic University of Korea Incheon St. Mary's Hospital (KR)
  • The Catholic University of Korea Seoul St. Mary's Hospital (KR)
  • The Catholic University of Korea Yeouido St. Mary's Hospital (KR)
Corresponding author
Park, Cheol Whee
Venue
Journal of the American Society of Nephrology
Published
2018-01-12
Volume
29
Issue
4
Pages
1108-1127
ISSN
  • 1046-6673 (ISSN-L)
  • 1533-3450
OpenAlex
W2783996679
Cited by
229
References
40
Citations by year
2026: 19 · 2025: 31 · 2024: 41 · 2023: 28 · 2022: 30 · 2021: 23 · 2020: 28 · 2019: 22 · 2018: 7
FWCI
16.38
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Society of Nephrology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Yonsei University
Topics
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
Keywords
AdipoRon, adiponectin receptor agonist, diabetic nephropathy, type 2 diabetes, AMPK, PPARα, CaMKKβ, LKB1, AdipoR1, AdipoR2, glomerular endothelial cells, podocytes, oxidative stress, apoptosis, endothelial dysfunction, intracellular calcium, cardioprotection, db/db mice
MeSH terms
Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Glucose, Humans, Male, Mice, Inbred C57BL, Mice, Obese, Phosphorylation, Piperidines, Protein Processing, Post-Translational, Apoptosis, Protein Serine-Threonine Kinases, Oxidative Stress, Endothelial Cells, PPAR alpha, Podocytes, Mice, Adiponectin, Receptors, Leptin, Receptors, Adiponectin, Calcium-Calmodulin-Dependent Protein Kinase Kinase, AMP-Activated Protein Kinases

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