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

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dc.contributor.author Lindfors, S
dc.contributor.author Polianskyte-Prause, Z
dc.contributor.author Bouslama, R
dc.contributor.author Lehtonen, E
dc.contributor.author Mannerla, M
dc.contributor.author Nisen, H
dc.contributor.author Tienari, J
dc.contributor.author Salmenkari, H
dc.contributor.author Forsgard, R
dc.contributor.author Mirtti, T
dc.contributor.author Lehto, M
dc.contributor.author Groop, PH
dc.contributor.author Lehtonen, S
dc.date.accessioned 2021-10-28T11:21:01Z
dc.date.available 2021-10-28T11:21:01Z
dc.date.issued 2021-08
dc.identifier.citation 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
dc.identifier.other PURE: 169854517
dc.identifier.other PURE UUID: 9cba2242-b557-4e66-a690-cb1230e70628
dc.identifier.other RIS: urn:B8722D7A1B3B55A26DF88C34AB211F44
dc.identifier.other WOS: 000650115800001
dc.identifier.other ORCID: /0000-0003-0455-9891/work/102234393
dc.identifier.other ORCID: /0000-0003-4189-2415/work/102235204
dc.identifier.other ORCID: /0000-0002-2024-0760/work/102236625
dc.identifier.other ORCID: /0000-0002-1905-918X/work/102237357
dc.identifier.uri http://hdl.handle.net/10138/335793
dc.description.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. en
dc.format.extent 14
dc.language.iso eng
dc.relation.ispartof Diabetologia
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Adiponectin
dc.subject AdipoRon
dc.subject Diabetes
dc.subject Diabetic kidney disease
dc.subject Inflammation
dc.subject Inflammatory cytokines
dc.subject LPS
dc.subject Obesity
dc.subject Obesity-related kidney disease
dc.subject Podocyte
dc.subject DIABETIC-NEPHROPATHY
dc.subject KIDNEY-DISEASE
dc.subject TNF-ALPHA
dc.subject PROGRESSION
dc.subject EXPRESSION
dc.subject GENE
dc.subject ALBUMINURIA
dc.subject DEFICIENCY
dc.subject MECHANISMS
dc.subject INSIGHTS
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo en
dc.type Article
dc.contributor.organization Doctoral Programme in Biomedicine
dc.contributor.organization Sanna Lehtonen research group
dc.contributor.organization CAMM - Research Program for Clinical and Molecular Metabolism
dc.contributor.organization Medicum
dc.contributor.organization Department of Pathology
dc.contributor.organization Doctoral Programme in Clinical Research
dc.contributor.organization Clinicum
dc.contributor.organization HUS Abdominal Center
dc.contributor.organization HUSLAB
dc.contributor.organization Department of Pharmacology
dc.contributor.organization Research Programs Unit
dc.contributor.organization Research Program in Systems Oncology
dc.contributor.organization Doctoral Programme in Integrative Life Science
dc.contributor.organization Doctoral Programme in Population Health
dc.contributor.organization Diabetes and Obesity Research Program
dc.contributor.organization Department of Medicine
dc.contributor.organization Per Henrik Groop / Principal Investigator
dc.contributor.organization Doctoral Programme in Drug Research
dc.contributor.organization Biosciences
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1007/s00125-021-05473-9
dc.relation.issn 0012-186X
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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