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

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-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/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-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

Neutralizing MIP3αReduces Renal Immune Cell Infiltration and Progressive Renal Injury in Young Obese Dahl Salt-Sensitive Rats

“…While the current study specifically focused on the effects of MIP3a blockade on renal injury in young obese SS LepR mutant rats, we would speculate that similar results would be observed in older SS LepR mutant rats. Inflammation is known to contribute to renal injury in various adult animal models of obesity (Fernández-Sánchez et al, 2011;Lindfors et al, 2021;Wang et al, 2015). To the best of our knowledge, this is the first study to demonstrate a role for MIP3a in the early development of renal injury associated with obesity.…”

Obesity-related kidney disease: Beyond hypertension and insulin-resistance

“…The molecule berberine enhances adiponectin signaling through AMPK to ameliorate renal pathology in diabetic mice ( 107 ). In animal models of diabetic nephropathy and obesity, the AMPK agonist PF-06409577 and adiponectin receptor agonist AdipoRon reduce proteinuria, inflammation, and renal fibrosis ( 108 – 110 ). These results suggest that targeting adiponectin receptors or AMPK directly may be beneficial in obesity- and diabetes-related kidney disease.…”

The role and mechanisms of gut microbiota in diabetic nephropathy, diabetic retinopathy and cardiovascular diseases

“…T2DM is characterized by a compromised intestinal barrier and elevated LPS levels, which contribute to systemic and local low-grade inflammation, thereby promoting the progress of diabetes and subsequent DN ( Zihan and Feng, 2016 ; Feng et al, 2019 ). LPS administration was shown to enhance urinary albumin excretion and renal injury ( Sawa et al, 2014 ; Lindfors et al, 2021 ). Several studies showed the increased intestinal permeability and elevated systemic LPS levels in the DN mice model; notably, improving the gut barrier alleviated DN ( Feng et al, 2019 ; Li et al, 2020a ; Gao et al, 2021 ).…”