Our study provides the first evidence of PEPT2-mediated uptake of polymyxins and contributes to a better understanding of the accumulation of polymyxins in renal tubular cells.

No abstract

Diabetes mellitus is a chronic metabolic disorder that significantly affects human health and well-being. The Solute carrier transporters (SLCs), particularly the Organic anion/cation transporters (Oats/Octs/Octns), Organic anion transporting polypeptides (Oatps) and Oligopeptide transporters (Pepts) are essential membrane proteins responsible for cellular uptake of many endogenous and exogenous substances such as clinically important drugs. They are widely expressed in mammalian key organs especially the kidney and liver, in which they facilitate the influx of various drug molecules, thereby determining their distribution and elimination in body. The altered expression of SLCs in diabetes mellitus could have a profound and clinically significant influence on drug therapies. In this study, we extensively investigated the renal and hepatic expression of twenty essential SLCs in the type 1 diabetic Ins2Akita murine model that develops both hyperglycemia and diabetes-related complications using real-time PCR and immunoblotting analysis. We found that the renal expression of mOatp1a1, mOatp1a6, mOat1, mOat3, mOat5, mOct2 and mPept2 was decreased; while that of mPept1 was increased at the mRNA level in the diabetic mice compared with non-diabetic controls. We found up-regulated mRNA expression of mOatp1a4, mOatp1c1, mOctn2, mOct3 and mPept1 as well as down-regulation of mOatp1a1 in the livers of diabetic mice. We confirmed the altered protein expression of several SLCs in diabetic mice, especially the decreased renal and hepatic expression of mOatp1a1. We also found down-regulated protein expression of mOat3 and mOctn1 in the kidneys as well as increased protein expression of mOatp1a4 and mOct3 in the livers of diabetic mice. Our findings contribute to better understanding the modulation of SLC transporters in type 1 diabetes mellitus, which is likely to affect the pharmacokinetic performance of drugs that are transported by these transporters and therefore, forms the basis of future therapeutic optimization of regimens in patients with type 1 diabetes mellitus.

OATs are known to mediate uptake of water-soluble, negatively charged organic molecules with low molecular weight such as steroid hormones and their conjugates, biogenic amines, numerous drugs and toxins [6,7]. So far, there are nine human OAT isoforms identified with OAT1, OAT2, OAT3 and OAT4 better characterized [1,6]. Tissue distribution OAT1 was first discovered as a para-aminohippurate (PAH) transporter in 1997 [7-9], which is abundantly expressed at the basolateral membrane of renal proximal tubular cells [10-15]. OAT2 was found to be predominantly expressed in the liver and also located at the blood-facing membrane of renal tubular cells [16,17]. OAT3 is widely expressed in the kidney, brain and liver [18]. OAT4 distributes at the apical membrane of renal proximal tubular cells and the basolateral membrane of syncytiotrophoblasts in the placenta [12,19-22]. OAT5 and OAT7 are found in human liver, while OAT10 distributes at the apical membrane of renal proximal tubules cells [23-25].