Abstract
Aims/hypothesisChronic 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.MethodsWild-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.ResultsIn HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (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-κB-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 TNFα (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-1β, IL-18, IL-6 and IL-10.Conclusions/interpretationAdipoRon 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-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.Graphical abstract
Highlights
Obesity and diabetes are important risk factors for the development of chronic kidney disease [1]
Serum adiponectin concentration was lowered in high-fat diet (HFD)- and HFD-AdipoRon-fed mice in comparison with low-fat diet (LFD)-fed mice (ESM Table 3), whereas renal expression of AdipoR1, the predominantly expressed form of the adiponectin receptors in the kidney [8], did not differ between the groups (Fig. 1d,f)
We show that AdipoRon ameliorates renal inflammation and injury in HFD-fed mice, attenuates LPS-induced inflammation and dysfunction in cultured human podocytes, and suppresses LPS-induced inflammatory cytokine secretion in isolated human glomeruli
Summary
Obesity and diabetes are important risk factors for the development of chronic kidney disease [1]. Both conditions are characterised by increased serum levels of lipopolysaccharides (LPSs), a state recognised as metabolic endotoxaemia, and chronic low-grade inflammation [2,3,4,5], and share a common trigger for the progression of renal injury. In response to metabolic stress and inflammatory milieu, renal cells secrete proinflammatory molecules, which activate an innate immunity response and promote renal abnormalities [4, 5]. As adiponectin has anti-inflammatory properties [7], its deficiency may promote chronic inflammation
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