Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction

Cavaglieri, Rita C.; Day, Robert T.; Féliers, Denis; Abboud, Hanna E.

doi:10.1016/j.mce.2015.06.006

Cited by 63 publications

(82 citation statements)

References 30 publications

(34 reference statements)

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“…These results are consistent with a previous report where metformin treatment of UUO for 7 and 14 days attenuated the level of inflammatory markers TNFα and VCAM119. Furthermore, we observed differential changes in expression of the anti-inflammatory macrophage marker Mac-2 and the pro-inflammatory markers MCP-1 and Itgax, which increased and decreased respectively, with metformin treatment, indicating that metformin might play a role for the regulation of the subpopulations of macrophages.…”

Section: Discussionsupporting

confidence: 93%

“…This finding support the results of previous studies demonstrating that metformin can attenuate tubular damage, both in Zucker diabetic fatty (ZDF) rats37 and in a gentamicin-induced nephropathy model38. A recently published study evaluated the level of tubular dilation in UUO mice treated with metformin in a 7dUUO model, but they were not able to detect any significant attenuation of tubular dilation19. This finding may suggest that the metformin has minor effects on tubular dilation at more chronic stages of obstruction.…”

Section: Discussionsupporting

confidence: 87%

“…Alternatively, the difference could be explained by differences in the experimental protocol. In the mentioned study mice received metformin 1 day prior to obstruction at a dose of 200 mg/kg/day19 as compared with 7 days at 500 mg/kg/day in our study. Surprisingly, metformin did not affect the degree of apoptosis.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, it has also been demonstrated that metformin attenuates progression of fibrosis in dogs subjected to 14 days unilateral ureteral obstruction (UUO)17, as well as in mouse models of 7 and 14 days UUO1819.…”

mentioning

confidence: 99%

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Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

Christensen

Jensen

Jakobsen

et al. 2016

Sci Rep

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The type-2 diabetes drug metformin has proven to have protective effects in several renal disease models. Here, we investigated the protective effects in a 3-day unilateral ureteral obstruction (3dUUO) mouse model. Compared with controls, ureteral obstructed animals displayed increased tubular damage and inflammation. Metformin treatment attenuated inflammation, increased the anti-oxidative response and decreased tubular damage. Hepatic metformin uptake depends on the expression of organic cation transporters (OCTs). To test whether the effects of metformin in the kidney are dependent on these transporters, we tested metformin treatment in OCT1/2−/− mice. Even though exposure of metformin in the kidney was severely decreased in OCT1/2−/− mice when evaluated with [11C]-Metformin and PET/MRI, we found that the protective effects of metformin were OCT1/2 independent when tested in this model. AMP-activated protein kinase (AMPK) has been suggested as a key mediator of the effects of metformin. When using an AMPK-β1 KO mouse model, the protective effects of metformin still occurred in the 3dUUO model. In conclusion, these results show that metformin has a beneficial effect in early stages of renal disease induced by 3dUUO. Furthermore, these effects appear to be independent of the expression of OCT1/2 and AMPK-β1, the most abundant AMPK-β isoform in the kidney.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

See 2 more Smart Citations

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

Christensen

Jensen

Jakobsen

et al. 2016

Sci Rep

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show abstract

“…In the present study, we prepared a unilateral ureteral obstructive (UUO) rat model, a widely used animal model to study kidney disease [34], and hypothesized to treat UUO rat model using the CBA-conjugated PSGT-mediated delivery of hepatocyte growth factor (HGF) gene utilizing the concept of kidney-specific targeting. We used HGF as a potential genetic material to ameliorate UUO in rat because several previous gene therapy studies showed that HGF blockades the progression of chronic obstructive nephropathy [35e37].…”

Section: Introductionmentioning

confidence: 99%

A high affinity kidney targeting by chitobionic acid-conjugated polysorbitol gene transporter alleviates unilateral ureteral obstruction in rats

et al. 2016

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Metformin inhibits high glucose‐induced apoptosis of renal podocyte through regulating miR‐34a/SIRT1 axis

Zhuang,

Sun,

et al. 2024

Immunity Inflam & Disease

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BackgroundPrevious studies have reported SIRT1 was inversely modulated by miR‐34a, However, mechanism of metformin (MFN)'s renal podocyte protection under high glucose (HG) conditions and the connection between miR‐34a and SIRT1 expression in diabetic nephropathy (DN) remain unclear.MethodWe aimed to further elucidate the role of miR‐34a in HG‐treated podocytes in DN. A conditionally immortalized human podocyte cell line was cultivated in d‐glucose (30 mM).ResultsMicroarray and RT‐qPCR revealed that miR‐34a was downregulated in HG‐treated podocytes. Additionally, miR‐34a levels increased in MFN‐treated HG‐induced podocytes. CCK‐8 assay, colony formation assay, flow cytometry, and Western blot detection showed that HG treatment reduced cell viability and promoted via HG treatment, and MFN treatment reversed this phenotypic change. MiR‐34a upregulation caused restored cell viability and suppressed cell apoptosis in HG‐treated podocytes, and miR‐34a downregulation led to damaged cell survival and induced apoptosis in MFN‐administered and HG‐treated podocytes. The dual luciferase reporter assay showed that SIRT1 3′‐UTR was a direct miR‐34a target. Further studies demonstrated an elevation in SIRT1 levels in HG‐exposed podocytes, whereas MFN treatment decreased SIRT1 levels. In addition, miR‐34a upregulation led to reduced SIRT1 expression, whereas miR‐34a inhibition increased SIRT1 levels in cells. MFN‐induced miR‐34a suppresses podocyte apoptosis under HG conditions by acting on SIRT1.ConclusionThis study proposes a promising approach to interpret the mechanisms of action of the MFN‐miR‐34a axis involved in DN.

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Metformin prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction

Cited by 63 publications

References 30 publications

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

A high affinity kidney targeting by chitobionic acid-conjugated polysorbitol gene transporter alleviates unilateral ureteral obstruction in rats

Metformin inhibits high glucose‐induced apoptosis of renal podocyte through regulating miR‐34a/SIRT1 axis

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