Back to Search
Start Over
The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes
- Source :
- Journal of the American Society of Nephrology : JASN. 29(4)
- Publication Year :
- 2017
-
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 Ca(2+)/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 Ser(431)LKB1, phosphorylated Thr(172)AMPK, 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 Ca(2+) levels that activated a CaMKKβ/phosphorylated Ser(431)LKB1/phosphorylated Thr(172)AMPK/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 Ca(2+)/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Mice, Obese
Apoptosis
Calcium-Calmodulin-Dependent Protein Kinase Kinase
AMP-Activated Protein Kinases
Protein Serine-Threonine Kinases
Podocyte
Diabetic nephropathy
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Piperidines
Internal medicine
medicine
Animals
Humans
Diabetic Nephropathies
PPAR alpha
Phosphorylation
Protein kinase A
Cells, Cultured
Adiponectin receptor 1
Adiponectin
Chemistry
Podocytes
Glomerulosclerosis
Endothelial Cells
General Medicine
medicine.disease
AdipoRon
Mice, Inbred C57BL
Oxidative Stress
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Glucose
Basic Research
Lipotoxicity
Diabetes Mellitus, Type 2
Nephrology
030220 oncology & carcinogenesis
Receptors, Leptin
Receptors, Adiponectin
Protein Processing, Post-Translational
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 29
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....797c0c3b4412ca9fc15b52271f26aaa3