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二甲双胍通过 PPARα 调节 OCT-2 和 MATE-1 在小鼠肾脏中的表达。

PPARα-Dependent Modulation by Metformin of the Expression of OCT-2 and MATE-1 in the Kidney of Mice.

机构信息

Department of Biophysics, Federal University of São Paulo, 04039032 São Paulo, Brazil.

Department Cell Biology and Development, Institute of Biomedical Sciences, University of São Paulo, 05508000 São Paulo, Brazil.

出版信息

Molecules. 2020 Jan 17;25(2):392. doi: 10.3390/molecules25020392.

DOI:10.3390/molecules25020392
PMID:31963528
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7024194/
Abstract

Metformin is the first-line drug for type 2 diabetes mellitus control. It is established that this drug traffics through OCT-2 and MATE-1 transporters in kidney tubular cells and is excreted in its unaltered form in the urine. Hereby, we provide evidence that points towards the metformin-dependent upregulation of OCT-2 and MATE-1 in the kidney via the transcription factor proliferator-activated receptor alpha (PPARα). Treatment of wild type mice with metformin led to the upregulation of the expression of OCT-2 and MATE-1 by 34% and 157%, respectively. An analysis in a kidney tubular cell line revealed that metformin upregulated PPARα and OCT-2 expression by 37% and 299% respectively. MK-886, a PPARα antagonist, abrogated the OCT-2 upregulation by metformin and reduced MATE-1 expression. Conversely, gemfibrozil, an agonist of PPARα, elicited the increase of PPARα, OCT-2, and MATE-1 expression by 115%, 144%, and 376%, respectively. PPARα knockout mice failed to upregulate both the expression of OCT-2 and MATE-1 in the kidney upon metformin treatment, supporting the PPARα-dependent metformin upregulation of the transporters in this organ. Taken together, our data sheds light on the metformin-induced mechanism of transporter modulation in the kidney, via PPARα, and this effect may have implications for drug safety and efficacy.

摘要

二甲双胍是 2 型糖尿病控制的一线药物。现已确定，该药物通过肾脏管状细胞中的 OCT-2 和 MATE-1 转运体进行转运，并以其未改变的形式从尿液中排出。因此，我们提供的证据表明，二甲双胍通过转录因子过氧化物酶体增殖物激活受体α（PPARα）依赖性地上调肾脏中的 OCT-2 和 MATE-1。用二甲双胍治疗野生型小鼠可使 OCT-2 和 MATE-1 的表达分别上调 34%和 157%。在肾小管细胞系中的分析表明，二甲双胍分别使 PPARα 和 OCT-2 的表达上调 37%和 299%。PPARα 拮抗剂 MK-886 可阻断二甲双胍引起的 OCT-2 上调并降低 MATE-1 的表达。相反，PPARα 的激动剂吉非贝齐可使 PPARα、OCT-2 和 MATE-1 的表达分别增加 115%、144%和 376%。在二甲双胍治疗后，PPARα 敲除小鼠未能使肾脏中 OCT-2 和 MATE-1 的表达上调，这支持了 PPARα 依赖性二甲双胍对该器官中转运体的上调作用。总之，我们的数据阐明了二甲双胍通过 PPARα 诱导肾脏中转运体调节的机制，这一效应可能对药物安全性和疗效有影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/27baf6030d8c/molecules-25-00392-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/5c5aa25b7976/molecules-25-00392-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/eb5a0ce995fa/molecules-25-00392-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/c6bcd8d0fe95/molecules-25-00392-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/27baf6030d8c/molecules-25-00392-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/5c5aa25b7976/molecules-25-00392-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/eb5a0ce995fa/molecules-25-00392-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/c6bcd8d0fe95/molecules-25-00392-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46d7/7024194/27baf6030d8c/molecules-25-00392-g004.jpg

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