Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients

Milaş, Oana; Gădălean, Florica; Vlad, Adrian; Dumitraşcu, Victor; Velciov, Silvia; Gluhovschi, Cristina; Bob, Flaviu; Popescu, Roxana; Ursoniu, Sorin; Jianu, Dragoș Cătălin; Matusz, Petru; Pusztai, Agneta-Maria; Secara, Alina; Simulescu, Anca; Stefan, Maria; Patruica, Mihaela; Petrica, Flaviu; Vlad, Daliborca; Petrică, Ligia

doi:10.1016/j.jdiacomp.2019.107479

Cited by 45 publications

(35 citation statements)

References 25 publications

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“…**p < 0.01 and ***p < 0.001 vs LFD. † p < 0.05, † † p < 0.01 and † † † p < 0.001 vs HFD severity of diabetic glomerular injury [34,35]. Interestingly, studies on obese individuals with pre-existing renal impairment undergoing bariatric surgery indicate that a reduction of renal inflammation may associate with improvements in renal function [3].…”

Section: Discussionmentioning

confidence: 99%

“…Studies on obese or diabetic animal models [ 5 , 28 – 30 ] and clinical trials targeting proinflammatory molecules in diabetic kidney disease (DKD) [ 5 ] suggest that proinflammatory cytokines directly contribute to the progression of renal injury. Proinflammatory cytokines and related molecules are upregulated in the glomeruli of individuals with obesity- or diabetes-related kidney disease [ 31 – 33 ] and associate with the severity of diabetic glomerular injury [ 34 , 35 ]. Interestingly, studies on obese individuals with pre-existing renal impairment undergoing bariatric surgery indicate that a reduction of renal inflammation may associate with improvements in renal function [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…IL-1β and IL-18 amplify the immune response by acting as costimulatory molecules for T cells and B cells. Urinary and plasma IL-1 levels in T2D patients are associated with podocyte and proximal tubular epithelial cell injury markers [ 59 ]. IL-18 is a member of the IL-1 superfamily and stimulates interferon-γ (IFN-γ) release and modulates innate and adaptive immune cells.…”

Section: The Role Of Inflammation In the Pathophysiology Of Dkdmentioning

confidence: 99%

The role of inflammation in diabetic kidney disease

Jung

Moon

2021

Korean J Intern Med

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Diabetic kidney disease (DKD) has been the leading cause of chronic kidney disease for over 20 years. Yet, over these two decades, the clinical approach to this condition has not much improved beyond the administration of glucose-lowering agents, renin-angiotensin-aldosterone system blockers for blood pressure control, and lipid-lowering agents. The proportion of diabetic patients who develop DKD and progress to end-stage renal disease has remained nearly the same. This unmet need for DKD treatment is caused by the complex pathophysiology of DKD, and the difficulty of translating treatment from bench to bed, which further adds to the growing argument that DKD is not a homogeneous disease. To better capture the full spectrum of DKD in our design of treatment regimens, we need improved diagnostic tools that can better distinguish the subgroups within the condition. For instance, DKD is typically placed in the broad category of a non-inflammatory kidney disease. However, genome-wide transcriptome analysis studies consistently indicate the inflammatory signaling pathway activation in DKD. This review will utilize human data in discussing the potential for redefining the role of inflammation in DKD. We also comment on the therapeutic potential of targeted anti-inflammatory therapy for DKD.

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“…Recent studies have linked inflammation to the development of a number of important diseases [1][2][3][4]. Inflammation can be induced by various stimuli, such as damage, pathogens, and their products, and is often accompanied by immune disorders [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Astragalus membranaceusInjection Suppresses Production of Interleukin-6 by Activating Autophagy through the AMPK-mTOR Pathway in Lipopolysaccharide-Stimulated Macrophages

Zhang

Tang

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Astragalus membranaceus (AM), used in traditional Chinese medicine, has been shown to enhance immune functions, and recently, its anti-inflammatory effects were identified. However, the mechanisms of action remain unclear. Most studies have shown that autophagy might be involved in the immune response of the body, including inflammation. Here, we developed an inflammatory model by stimulating macrophages with lipopolysaccharides (LPS) to explore the anti-inflammatory effect and mechanisms of AM injection from the perspective of the regulation of autophagy. Immunoblot, immunofluorescence, and ELISA were used to determine the effects of AM injection on the production of interleukin-6 (IL-6) and alterations of autophagy markers. It was found that AM injection reduced the expression of IL-6 in LPS-stimulated macrophages and reversed the LPS-induced inhibition of cellular autophagy. After treatment with inhibitors of signaling pathways, it was shown that LPS downregulated autophagy and upregulated the production of IL-6 in macrophages via the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. AM injection reversed the effects of LPS by activating the AMP-activated protein kinase (AMPK) instead of inhibiting Akt. These results were further confirmed by testing activators and siRNA silencing of AMPK. Hence, these 2 distinct signaling molecules appear to exert opposite effects on mTOR, which integrates information from multiple upstream signaling pathways, negatively regulating autophagy. In addition, we demonstrated that autophagy might play a key role in regulating the production of IL-6 by testing activators and inhibitors of autophagy and siRNA silencing of ATG5. These findings showed that AM injection might enhance autophagy by activating AMPK and might further play a repressive effect on the LPS-stimulated expression of IL-6. This study explored the relationship between autophagy, signaling pathways, and the production of inflammatory factors in a model of endotoxin infection and treatment with AM injection.

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Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients

Cited by 45 publications

References 25 publications

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

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

The role of inflammation in diabetic kidney disease

Astragalus membranaceusInjection Suppresses Production of Interleukin-6 by Activating Autophagy through the AMPK-mTOR Pathway in Lipopolysaccharide-Stimulated Macrophages

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