Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease

Tserga, Aggeliki; Pouloudi, Despoina; Saulnier-Blache, Jean Sébastien; Stroggilos, Rafael; Theochari, Irene; Gakiopoulou, Harikleia; Mischak, Harald; Zoidakis, Jérôme; Schanstra, Joost P.; Vlahou, Antonia; Makridakis, Manousos

doi:10.3390/biomedicines10020216

Cited by 4 publications

(8 citation statements)

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“…From the proteomics data of the published study on the Ins2Akita model [33], we observed an upregulation of proteins related to the complement cascade, fibrosis, and inflammation (Table 1). Specifically, C3, C4B, and IGHM were upregulated in glomeruli of 2-month-old mice and C4B and IGHM in glomeruli of 4-month-old mice vs. controls (Table 1).…”

Section: Complement Cascade Inflammation and Fibrosis Correlate In Dk...mentioning

confidence: 88%

“…Given the conservation of the observed changes in the animal models and humans, a further investigation of links between the processes of complement activation, fibrosis, and inflammation was performed. As a first step, a Spearman rho correlation analysis was performed for all detected proteins representing the three processes in 2-months-old mice, 4-months-old mice, and both groups combined [33]. As shown in Table 3, a positive and significant correlation of the expression of the three proteins of the complement cascade and fibrosis-related (Tables 3 and S1) or inflammation-related proteins (Tables 4 and S2) in early DKD in Ins2Akita mice could be observed.…”

Section: Positive Correlation Of Expression Of Complement Proteins Wi...mentioning

confidence: 99%

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Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

Tserga,

Saulnier-Blache,

Palamaris

et al. 2024

IJMS

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Diabetic kidney disease (DKD) is characterized by histological changes including fibrosis and inflammation. Evidence supports that DKD is mediated by the innate immune system and more specifically by the complement system. Using Ins2Akita T1D diabetic mice, we studied the connection between the complement cascade, inflammation, and fibrosis in early DKD. Data were extracted from a previously published quantitative-mass-spectrometry-based proteomics analysis of kidney glomeruli of 2 (early DKD) and 4 months (moderately advanced DKD)-old Ins2Akita mice and their controls A Spearman rho correlation analysis of complement- versus inflammation- and fibrosis-related protein expression was performed. A cross-omics validation of the correlation analyses’ results was performed using public-domain transcriptomics datasets (Nephroseq). Tissue sections from 43 patients with DKD were analyzed using immunofluorescence. Among the differentially expressed proteins, the complement cascade proteins C3, C4B, and IGHM were significantly increased in both early and later stages of DKD. Inflammation-related proteins were mainly upregulated in early DKD, and fibrotic proteins were induced in moderately advanced stages of DKD. The abundance of complement proteins with fibrosis- and inflammation-related proteins was mostly positively correlated in early stages of DKD. This was confirmed in seven additional human and mouse transcriptomics DKD datasets. Moreover, C3 and IGHM mRNA levels were found to be negatively correlated with the estimated glomerular filtration rate (range for C3 rs = −0.58 to −0.842 and range for IGHM rs = −0.6 to −0.74) in these datasets. Immunohistology of human kidney biopsies revealed that C3, C1q, and IGM proteins were induced in patients with DKD and were correlated with fibrosis and inflammation. Our study shows for the first time the potential activation of the complement cascade associated with inflammation-mediated kidney fibrosis in the Ins2Akita T1D mouse model. Our findings could provide new perspectives for the treatment of early DKD as well as support the use of Ins2Akita T1D in pre-clinical studies.

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Section: Complement Cascade Inflammation and Fibrosis Correlate In Dk...mentioning

confidence: 88%

Section: Positive Correlation Of Expression Of Complement Proteins Wi...mentioning

confidence: 99%

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

Tserga,

Saulnier-Blache,

Palamaris

et al. 2024

IJMS

Self Cite

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“…13 TGF-β, JAK/STAT, Notch and other signaling pathways play a role in renal fibrosis. 14 IL-6 is a pro-inflammatory cytokine whose main biological function is to regulate immune response and inflammatory response. IL-6 can not only directly stimulate the proliferation of mesangial cells, damage islet cells and destroy islet function, but also damage renal vascular endothelial cells and promote renal interstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

The Expression of miR-377-3p in Patients with DKD and the Regulatory Mechanism of miR-377-3p on the Inflammatory Response of HK-2 Cells Through TGF-β

Xing,

Lu,

Liu

et al. 2024

DMSO

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Objective The purpose of the study was to investigate the expression levels and correlation of inflammatory factors such as miR-377-3p and TGF-β in patients with diabetic kidney disease (DKD), and to investigate the regulatory mechanism of transfection of miR-377-3p on the inflammatory response of HK-2 cell induced by high glucose. Methods According to UACR, patients were divided into normal albuminuria group (Con, n = 29), microalbuminuria group (Micro, n = 31) and macroalbuminuria group (Macro, n = 30), analyzed the correlation and influencing factors between DKD and inflammatory factor. HK-2 cells were randomly divided into four groups: normal control group (NC), high glucose group (HG), miR-377-3p overexpression group (MIN), and miR-377-3p inhibition group (IN). After transfection of miR-377-3p mimics and inhibitors, the contents of TGF-β, IL-6 and IL-18 were detected by RT-PCR and Western blot. Results The levels of miR-377-3p, TGF-β, IL-6 and IL-18 in both Micro group and Macro group were significantly higher than those in Con group (P < 0.05); Pearson correlation analysis showed that miR-377-3p was positively correlated with UACR, TG, TGF-β, IL-6 and IL-18, and negatively correlated with GFR (P < 0.05). Cell experiment: RT-PCR and Western blot results showed that miR-377-3p, TGF-β, IL-6 and IL-18 in HG group were significantly higher than those in NC group (P < 0.05). After transfection with miR-377-3p inhibitor, the levels of miR-377-3p, TGF-β, IL-6 and IL-18 in IN group were significantly decreased compared with HG group and MIN group. Conclusion miR-377-3p expression was elevated both in serum of DKD patients and in HK-2 cells with high glucose induced injury, overexpression of miR-377-3p exacerbates the damage to HK-2 cells and promotes the progression of DKD. Silencing miR-377-3p can potentially regulate the levels of inflammatory factors in HK-2 cells by targeting downregulation of TGF-β expression, thereby mitigating the damage to HK-2 cells and delaying the development of diabetic kidney disease.

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“…However, diabetic mice with catalase KO were reported to show an increased proteinuria, attenuated renal function, increased serum FFAs, and increased mitochondrial reactive oxygen species (ROS) [30]. Also, in two types of DM mouse model, the hallmark proteins of peroxisomal oxidation were found to be decreased and this phenomenon was validated from the kidney tissues of DKD patients [31].…”

Section: Fa Oxidation (Fao)mentioning

confidence: 98%

Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

Chae,

Kim,

Park

2023

Antioxidants

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Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD.

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Proteomic Analysis of Mouse Kidney Tissue Associates Peroxisomal Dysfunction with Early Diabetic Kidney Disease

Cited by 4 publications

References 86 publications

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

Complement Cascade Proteins Correlate with Fibrosis and Inflammation in Early-Stage Type 1 Diabetic Kidney Disease in the Ins2Akita Mouse Model

The Expression of miR-377-3p in Patients with DKD and the Regulatory Mechanism of miR-377-3p on the Inflammatory Response of HK-2 Cells Through TGF-β

Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

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