Metformin modulates immune cell infiltration into the kidney during unilateral ureteral obstruction in mice

Christensen, Michael; Nørgård, Mikkel Ø.; Jensen, Michael Schou; Møller, Bjarne Kuno; Nørregaard, Rikke

doi:10.14814/phy2.14141

Cited by 18 publications

(15 citation statements)

References 34 publications

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“…The anti-oncogene effects of metformin have been suggested to involve inhibition of the STAT3 pathway, which can also prevent monocyte-to-macrophage differentiation [16,22]. We previously postulated that metformin attenuated immune cell infiltration by reducing pSTAT3 expression [14]. However, we did not observe any immunoregulatory effects of phenformin, despite a significant impact on pSTAT3 levels.…”

Section: Discussioncontrasting

confidence: 80%

“…We have recently shown that metformin decreases the expression of VCAM and ICAM and limits immune cell infiltration into UUO kidneys [6]. In addition, metformin modulates immune cell composition on a systemic level, indicating whole-body mechanisms underlying the renoprotective effects of metformin [14]. However, our current data indicate that the renoprotective effects of phenformin are independent of immunoregulatory effects.…”

Section: Discussionmentioning

confidence: 53%

“…We previously demonstrated that metformin reduces the number of immune cells in UUO kidneys [14]. Here we investigated whether phenformin had a similar effect.…”

Section: Impact Of Metformin and Phenformin On Immune Cell Infiltrationmentioning

confidence: 89%

“…All data were time-gated to exclude any abnormalities, as well as doublets and dead cells. The SHAM, UUO, and metformin groups have previously been used in a different study [14], but all groups, including the phenformin group, were analyzed at the same time.…”

Section: Cell Preparation and Flow Cytometrymentioning

confidence: 99%

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Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration

et al. 2020

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Phenformin and metformin are antihyperglycemic drugs that belong to the class of biguanides. Previously, we demonstrated that metformin elicits renoprotective effects in unilateral ureteral obstructed mice by reducing the infiltration of immune cells into the kidney. Since phenformin is a more potent drug as compared to metformin, we investigated the renoprotective properties of phenformin. We studied the efficacy of both drugs using mice that underwent unilateral ureteral obstruction. Renal damage was evaluated on RNA and protein level by qPCR, Western blotting, and immunohistochemistry. Moreover, we studied immune cell infiltration using flow cytometry. Both biguanides significantly reduced UUO-induced kidney injury, as illustrated by a reduction in KIM-1 protein expression. In addition, both metformin and phenformin impacted the gene expression of several inflammatory markers but to a different extent. Moreover, in contrast to metformin, phenformin did not impact immune cell infiltration into UUO kidneys. In conclusion, we demonstrated that phenformin has similar renoprotective effects as metformin, but the mechanism of action differs, and phenformin is more potent. The beneficial effects of phenformin are probably due to inhibition of the STAT3 pathway and mitochondrial complex I. Further research is needed to unveil the therapeutic potential of phenformin for the treatment of renal injury, either at low, non-toxic concentrations or as part of a combination therapy.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 53%

“…We previously demonstrated that metformin reduces the number of immune cells in UUO kidneys [14]. Here we investigated whether phenformin had a similar effect.…”

Section: Impact Of Metformin and Phenformin On Immune Cell Infiltrationmentioning

confidence: 89%

Section: Cell Preparation and Flow Cytometrymentioning

confidence: 99%

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Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration

et al. 2020

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“…They observed that metformin attenuates these inductions by UUO in AMPK-β1-deficient mice, suggesting that the renoprotective effects of metformin are independent of OCT1/2 and AMPK [ 72 ]. Accordingly, they reported that metformin inhibits STAT3-mediated immune cell infiltration, tubular damage and fibrosis in a UUO mice model, which may explain the AMPK-independent mechanisms [ 73 ]. Feng et al showed that metformin attenuates UUO-induced renal fibrosis in AMPKα2-deficient mice [ 74 ].…”

Section: Basic Mechanisms Underlying the Effects Of Metformin On Dmentioning

confidence: 99%

Significance of Metformin Use in Diabetic Kidney Disease

Kawanami

Yuasa

Tanabe

2020

IJMS

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Metformin is a glucose-lowering agent that is used as a first-line therapy for type 2 diabetes (T2D). Based on its various pharmacologic actions, the renoprotective effects of metformin have been extensively studied. A series of experimental studies demonstrated that metformin attenuates diabetic kidney disease (DKD) by suppressing renal inflammation, oxidative stress and fibrosis. In clinical studies, metformin use has been shown to be associated with reduced rates of mortality, cardiovascular disease and progression to end-stage renal disease (ESRD) in T2D patients with chronic kidney disease (CKD). However, metformin should be administered with caution to patients with CKD because it may increase the risk of lactic acidosis. In this review article, we summarize our current understanding of the safety and efficacy of metformin for DKD.

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Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

Sun

Wei

et al. 2022

Cell. Mol. Life Sci.

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Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

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Metformin modulates immune cell infiltration into the kidney during unilateral ureteral obstruction in mice

Cited by 18 publications

References 34 publications

Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration

Phenformin Attenuates Renal Injury in Unilateral Ureteral Obstructed Mice without Affecting Immune Cell Infiltration

Significance of Metformin Use in Diabetic Kidney Disease

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

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