Mechanism and application of metformin in kidney diseases: An update

Song, Anni; Zhang, Chun; Meng, Xianfang

doi:10.1016/j.biopha.2021.111454

Cited by 64 publications

(49 citation statements)

References 167 publications

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“…As in the case of several other mechanisms discussed for SGLT2i and GLP1-R agonists in this review, the protective mechanisms of liraglutide also depended on the AMPK signaling activation [ 121 ]. Intriguingly, the same mechanism, i.e., AMPK-dependent inhibition of EMT in renal tubular epithelial cells, was described some years ago for metformin, the drug that cannot be used in patients with advanced CKD but undoubtably has nephroprotective potential in earlier stages of the disease [ 122 ].…”

Section: Glp1r Agonists As Antioxidative and Anti-inflammatory Agents In Other Tissues And Organsmentioning

confidence: 93%

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Winiarska

Knysak

Nabrdalik

et al. 2021

IJMS

110

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The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

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Section: Glp1r Agonists As Antioxidative and Anti-inflammatory Agents In Other Tissues And Organsmentioning

confidence: 93%

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Winiarska

Knysak

Nabrdalik

et al. 2021

IJMS

110

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show abstract

“…Also, an active role is effectuated in high-glucose-induced renal tubular epithelial cells and db/db mice model through the MBNL1/miR-130a-3p/STAT3 pathway ( Jiang et al, 2020 ). Metformin also reduces the loss of podocytes, mesangial cell apoptosis, and renal tubular epithelial cell senescence through the AMPK signal transduction pathway and exerts a renal protective role in DKD ( Song et al, 2021 ). The anti-inflammatory and anti-fibrosis mechanisms of metformin and alleviation of cellular senescence in DKD are yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Metformin Improves the Senescence of Renal Tubular Epithelial Cells in a High-Glucose State Through E2F1

Liang

Feng

et al. 2022

Front. Pharmacol.

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Diabetic kidney disease is a major cause of chronic kidney condition and the most common complication of diabetes. The cellular senescence participates in the process of diabetic kidney disease, but the specific mechanism is not yet clear. Cell cycle-related protein E2F transcription factor 1 (E2F1) is a member of the E2F transcription factor family, it plays a key role in cellular damage under HG conditions. In this study, we explored whether metformin improves a high-glucose-induced senescence and fibrosis of renal tubular epithelial cells through cell cycle-related protein E2F1. In the in vivo experiments, the recombinant adeno-associated virus (AAV-shE2F1) knockdown E2F1 gene was injected into the tail vein of 16-weeks-old db/db mice for 8 weeks. The 16-week-old db/db mice were administered metformin (260 mg/kg/d) continuously for 8 weeks. The normal control group (NC) and diabetic model group (DM) were set up simultaneously. Mice renal tubular epithelial cells (mRTECs) were cultured in vitro. The cells were randomly divided into the following groups: normal glucose (NG, containing 5.5 mmol/L glucose), high glucose group (HG, containing 30 mmol/L glucose), NG/HG metformin intervention group (NG/HG + Met), NG/HG negative control siRNA transfection group (NG/HG + Control), NG/HG E2F1 siRNA transfection group (NG/HG + siRNA E2F1), HG metformin intervention and overexpression E2F1 plasmid transfection group (HG + Met + overexpress-E2F1). The expression of related indexes were detected by Western blot, real-time polymerase chain reaction (PCR), immunohistochemistry, and immunofluorescence. The results showed that E2F1 knockdown or metformin reduces the degree of renal fibrosis, DNA damage, and cellular senescence in the DM group; metformin also reduced the expression of E2F1. If E2F1 was overexpressed, the effects of metformin in delaying fibrosis and reducing DNA damage and cellular senescence could be weakened. Thus, metformin alleviates high-glucose-induced senescence and fibrosis of renal tubular epithelial cells by downregulating the expression of E2F1.

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“…The balance between pro- and anti-inflammatory mediators affects the tissue repair process after acute inflammatory injury, whereas an imbalanced inflammatory response can impede normal tissue repair as well as lead to abnormal remodeling and dysfunction. Ideally, the balance between pro- and anti-inflammatory mediators ensures the later repair of the renal tissue ( Song et al, 2021 ). However, in many cases, sustained secretion of the inflammation-associated fibrotic cytokines TGF-β and IL-13 trigger epithelial-mesenchymal transition ( Wang et al, 2019 ; Hu J. et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Intersection of Acute Kidney Injury and Non-Coding RNAs: Inflammation

Lin

Xia

et al. 2022

Front. Physiol.

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Acute renal injury (AKI) is a complex clinical syndrome, involving a series of pathophysiological processes, in which inflammation plays a key role. Identification and verification of gene signatures associated with inflammatory onset and progression are imperative for understanding the molecular mechanisms involved in AKI pathogenesis. Non-coding RNAs (ncRNAs), involved in epigenetic modifications of inflammatory responses, are associated with the aberrant expression of inflammation-related genes in AKI. However, its regulatory role in gene expression involves precise transcriptional regulation mechanisms which have not been fully elucidated in the complex and volatile inflammatory response of AKI. In this study, we systematically review current research on the intrinsic molecular mechanisms of ncRNAs that regulate the inflammatory response in AKI. We aim to provide potential research directions and strategies for developing ncRNA-targeted gene therapies as an intervention for the inflammatory damage in AKI.

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Mechanism and application of metformin in kidney diseases: An update

Cited by 64 publications

References 167 publications

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

Metformin Improves the Senescence of Renal Tubular Epithelial Cells in a High-Glucose State Through E2F1

The Intersection of Acute Kidney Injury and Non-Coding RNAs: Inflammation

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