Abstract
Organic cation transporter 2 (OCT2), encoded by the SLC22A2 gene, is the main cation transporter on the basolateral membrane of proximal tubular cells. OCT2 facilitates the entry step of the vectorial transport of most cations from the peritubular space into the urine. OCT2 downregulation in kidney disease models is apparent, yet not clear from a mechanistic vantage point. The aim of this study was to explore the role of inflammation, a common thread in kidney disease, and NF-kB in OCT2 modulation and tubular secretion. Among the OCTs, OCT2 was found consistently downregulated in the kidney of rats with chronic kidney disease (CKD) or acute kidney injury (AKI) and in patients diagnosed with CKD, and it was associated with the upregulation of TNFα renal expression. Exposure to TNFα reduced the expression and function of OCT2 in primary renal proximal tubule epithelial cells (RPTEC). Silencing or pharmacological inhibition of NF-kB rescued the expression of OCT2 in the presence of TNFα, indicating that OCT2 repression was NF-kB-dependent. In silico prediction coupled to gene reporter assay demonstrated the presence of at least one functional NF-kB cis-element upstream the transcription starting site of the SLC22A2 gene. Acute inflammation triggered by lipopolysaccharide injection induced TNFα expression and the downregulation of OCT2 in rat kidney. The inflammation did reduce the active secretion of the cation Rhodamine 123, with no impairment of the glomerular filtration. In conclusion, the NF-kB pathway plays a major role in the transcriptional regulation of OCT2 and, in turn, in the overall renal secretory capacity.
Highlights
Solutes are excreted from the body via the kidneys through three concerted processes: glomerular filtration, tubular secretion and reabsorption [1,2,3]
The protein expression level of Organic cation transporter 2 (OCT2) and OCT3, the two main polyspecific organic cation transporters expressed in human proximal tubular cells, was evaluated in biopsies from patients diagnosed with chronic kidney disease (CKD) and compared to that in pathologically normal renal tissue collected from patients with normal kidney function who underwent surgery for suspicion of renal cancer
The subcortical origin of the bioptic tissues was determined by assessing the mRNA level of the sodium/glucose cotransporter 1 (SGLT1), whose expression is confined to segment 3 of the cortex, and the sodium/glucose cotransporter 2 (SGLT2), expressed in segments 1 and 2, where OCT2 and OCT3 primarily localize
Summary
Solutes are excreted from the body via the kidneys through three concerted processes: glomerular filtration, tubular secretion and reabsorption [1,2,3]. Tubular secretion was demonstrated to be critical for the clearance of organic ions and even involved in the elimination of salt and water [5, 6]. For the most part, at the proximal tubule level, and, as demonstrated in stop-flow and micropuncture seminal studies in mammalian, fish, and avian kidneys, it seems relevant for positively charged solutes including endogenous substances, xenobiotics and drugs, the latter accounting for close to 40% of approved compounds with marketing authorization by regulatory agencies [7]. Extensive pharmacogenetic evidence indicates that among the OCTs, OCT2 is the primary route of renal elimination of several drugs to the point that guidance of drug regulatory agencies demands that each molecule in development be tested in vitro for inhibition of OCT2 transport activity in order to predict potential drug-drug interactions [9, 10]
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