Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo

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Lindfors , S , Polianskyte-Prause , Z , Bouslama , R , Lehtonen , E , Mannerla , M , Nisen , H , Tienari , J , Salmenkari , H , Forsgard , R , Mirtti , T , Lehto , M , Groop , PH & Lehtonen , S 2021 , ' Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo ' , Diabetologia , vol. 64 , no. 8 , pp. 1866-1879 . https://doi.org/10.1007/s00125-021-05473-9

Title: Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo
Author: Lindfors, S; Polianskyte-Prause, Z; Bouslama, R; Lehtonen, E; Mannerla, M; Nisen, H; Tienari, J; Salmenkari, H; Forsgard, R; Mirtti, T; Lehto, M; Groop, PH; Lehtonen, S
Other contributor: University of Helsinki, Doctoral Programme in Biomedicine
University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism
University of Helsinki, Doctoral Programme in Biomedicine
University of Helsinki, Medicum
University of Helsinki, Doctoral Programme in Clinical Research
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUSLAB
University of Helsinki, Clinicum
University of Helsinki, Research Programs Unit
University of Helsinki, Research Program in Systems Oncology
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUS Abdominal Center
University of Helsinki, Department of Pathology


















Date: 2021-08
Language: eng
Number of pages: 14
Belongs to series: Diabetologia
ISSN: 0012-186X
DOI: https://doi.org/10.1007/s00125-021-05473-9
URI: http://hdl.handle.net/10138/335793
Abstract: Aims/hypothesis Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist. Methods Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration. Results In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-kappa B p65 subunit (NF-kappa B-p65) (70%, p < 0.001), TNF alpha (48%, p < 0.01), IL-1 beta (51%, p < 0.001) and TGF beta (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-kappa B-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNF alpha (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1 beta, IL-18, IL-6 and IL-10. Conclusions/interpretation AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-kappa B-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNF alpha. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.
Subject: Adiponectin
AdipoRon
Diabetes
Diabetic kidney disease
Inflammation
Inflammatory cytokines
LPS
Obesity
Obesity-related kidney disease
Podocyte
DIABETIC-NEPHROPATHY
KIDNEY-DISEASE
TNF-ALPHA
PROGRESSION
EXPRESSION
GENE
ALBUMINURIA
DEFICIENCY
MECHANISMS
INSIGHTS
3121 General medicine, internal medicine and other clinical medicine
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