Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy

Wei, Tiantian; Yang, Luxi; Guo, Fan; Tao, Sibei; Cheng, Lu; Huang, Rongshuang; Ma, Liang; Fu, Ping

doi:10.1038/s41401-020-00520-4

Cited by 26 publications

(17 citation statements)

References 36 publications

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“…This study revealed that miR-155 was significantly elevated in serum and kidney specimens of DN mice and podocytes exposed to a high glucose environment. Microinflammation mediates an important function in DN podocyte injury [31,32]. This provided the basis of determining the relationship between miR-155 expression and the podocyte inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Wang

Gao

et al. 2021

Journal of Diabetes Research

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Objective. Microinflammation plays a crucial role in podocyte dysfunction in diabetic nephropathy, but its regulatory mechanism is still unclear. This study is aimed at discussing the mechanisms underlying the effect of miRNA-155 on podocyte injury to determine its potential as a therapeutic target. Methods. Cultured immortalized mouse podocytes and diabetic KK-Ay mice models were treated with a miR-155 inhibitor. Western blotting, real-time PCR, ELISA, immunofluorescence, and Luciferase reporter assay were used to analyze markers of inflammation cytokines and podocyte injury. Results. miRNA-155 was found to be highly expressed in serum and kidney tissue of mice with diabetic nephropathy and in cultured podocytes, accompanied by elevated levels of inflammatory factors. Inhibition of miRNA-155 can reduce proteinuria and ACR levels, diminish the secretion of inflammatory molecules, improve kidney function, inhibit podocyte foot fusion, and reverse renal pathological changes in diabetic nephropathy mice. Overexpression of miRNA-155 in vitro can increase inflammatory molecule production in podocytes and aggravates podocyte injury, while miRNA-155 inhibition suppresses inflammatory molecule production in podocytes and reduces podocyte injury. A luciferase assay confirmed that miRNA-155 could selectively bind to 3 ′ -UTR of SIRT1, resulting in decreased SIRT1 expression. In addition, SIRT1 siRNA could offset SIRT1 upregulation and enhance inflammatory factor secretion in podocytes, induced by the miRNA-155 inhibitor. Conclusions. These findings strongly support the hypothesis that miRNA-155 inhibits podocyte inflammation and reduces podocyte injury through SIRT1 silencing. miRNA-155 suppression therapy may be useful for the management of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Wang

Gao

et al. 2021

Journal of Diabetes Research

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“…A recent study revealed that mfat-1 mice and n-3 PUFAs-fed WT mice exhibited upregulated GPR120 expression in the adipose tissues [ 32 ] . Previous studies have reported that through the GPR120 signaling pathway, n-3 PUFAs pretreatment could inhibit downstream pro-inflammatory responses such as the phosphorylation of TAK1 and nuclear factor-κB (NF-κB) [ 33 – 34 ] . TAK1, has dual functions, i.e.…”

Section: Resultsmentioning

confidence: 99%

Protective effects on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice by alleviating neuroinflammation

et al. 2021

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Acute hypoxic-ischemic brain damage (HIBD) mainly occurs in adults as a result of perioperative cardiac arrest and asphyxia. The benefits of n-3 polyunsaturated fatty acids (n-3 PUFAs) in maintaining brain growth and development are well documented. However, possible protective targets and underlying mechanisms of mfat-1 mice on HIBD require further investigation. The mfat-1 transgenic mice exhibited protective effects on HIBD, as indicated by reduced infarct range and improved neurobehavioral defects. RNA-seq analysis showed that multiple pathways and targets were involved in this process, with the anti-inflammatory pathway as the most significant. This study has shown for the first time that mfat-1 has protective effects on HIBD in mice. Activation of a G protein-coupled receptor 120 (GPR120)-related anti-inflammatory pathway may be associated with perioperative and postoperative complications, thus innovating clinical intervention strategy may potentially benefit patients with HIBD.

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“…Macrophages are the principal type of immune cells that promote kidney damage in diabetes[ 34 , 35 ]. F4/80 is a macrophage-specific antigen that participates in the maturation and activation of this cell type.…”

Section: Discussionmentioning

confidence: 99%

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice

Li¹,

Liu²,

Zheng³

et al. 2022

WJD

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BACKGROUND Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury. AIM To elucidate whether clopidogrel is beneficial against DN by using a db / db mouse model. METHODS db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson’s trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1β mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry. RESULTS Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1β and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice ( P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice. CONCLUSION Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db / db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

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Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy

Cited by 26 publications

References 36 publications

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Inhibition of miRNA-155 Alleviates High Glucose-Induced Podocyte Inflammation by Targeting SIRT1 in Diabetic Mice

Protective effects on acute hypoxic-ischemic brain damage in mfat-1 transgenic mice by alleviating neuroinflammation

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice

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