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Analysis of the upstream regions of hMATE1 and rMate1 have identified critical regions responsible for basal promoter activity (SLC47A1: −65 to −25 and Slc47a1: −146 to −38) [68]. These regions lack canonical TATA and CCAAT boxes but instead contain two GC‐rich sites [68]. Basal promoter activity is increased with overexpression of the Sp1 transcription factor and blocked by mithramycin A, which is known to bind GS boxes and prevent Sp1 binding and activity [68]. Within the basal promoter region of hMATE1, there are two sites for Sp1 binding, both of which have been demonstrated to be functional based on mutagenesis studies [68]. Within the human population, there was a single‐nucleotide polymorphism (SNP) at position −32 (G/A) that reduces luciferase activity when expressed in vitro, likely due to impaired Sp1 activity [68].

Hepatocyte nuclear factor (HNF) 4 alpha has emerged as a novel transcriptional regulator of mMate1 [69]. ChIP‐Seq has revealed binding of HNF4 alpha within the region of Slc47a1 and Slc47a2. Inhibition of HNF4 alpha in embryonic rat kidney cultures markedly reduced rMate1 mRNA expression [69]. By comparison, over‐expression of HNF4 alpha in mouse embryonic fibroblasts increased mMate1 mRNA. Recognizing that HNF4 alpha is a master regulator of xenobiotic processing genes, it is possible the upregulation of mMate1 occurs directly or indirectly by activating upstream signaling paths.

The transcriptional regulator of stress responses, nuclear factor e2‐related factor 2 (NRF2), also influences MATE expression. Downregulation of NRF2 in human proximal tubule cells reduced hMATE2‐K mRNA [70]. Likewise, pharmacological activation of NRF2 or genetic disruption of its negative regulator KEAP1 induced the expression of hMATE2‐K mRNA. It has been presumed that stimulation of NRF2 signaling may be the mechanism by which hMATE2‐K levels are enhanced in response to shear stress when cultured in a microfluidic system [70]. The ability of NRF2 to similarly regulate MATE1 expression in human proximal tubule epithelial cells has been demonstrated after treatment with the pharmacological activator, bardoxolone‐methyl [71].

Two nuclear receptors have also emerged as potential regulators of Mate transporters, namely, the peroxisome proliferator‐activated receptor (PPAR) alpha and the farnesoid × receptor (FXR). Daily treatment of mice with metformin for 30 days increased mMate1 mRNA in the kidneys of wild‐type mice, with no change observed in mice lacking PPAR alpha [72]. This observation was further supported by the ability of the PPAR alpha agonist, gemfibrozil, to elevate mMate1 expression in mouse kidney tubular cells [72]. Likewise, treatment with obeticholic acid, a nonsteroidal agonist of FXR, increased the mRNA expression of Mate1 in the livers of rats [73].