Role of Organic Anion Transporter in Renal Tubular Injury---A Gateway to Hurt

The prevalence of chronic kidney disease (CKD) increased rapidly during the last decade in our country. The progression of CKD is heterogeneous with various paces and courses. Genetic predisposition is thought to be one of the causes. However, the genetic basis of the development and progression of CKD is not clear. The pathological course of CKD is a virtuous circle. Chronic kidney injury cause impaired renal function, which leads to uremic toxin accumulation. Current studies revealed that uremic toxins as indoxyl sulfate (IS) and p-cresol sulfate (PCS) could increase oxidative stress and induce cell apoptosis. Organic anion transporters (OATs) (SLC22A family) play crucial roles in the renal secretion of various drugs and uremic toxins. mRNA expression of the transporters can be a key factor regulating drug pharmacokinetics and uremic toxin secretion. We hypothesize that the variations in mRNA levels of OATs can affect the development and progression of CKD. However, the source of variations in mRNA levels of these transporters is unclear. In this study, we focused on single nucleotide polymorphisms (SNP) in the promoter region [regulatory SNPs (rSNPs)] of OAT1 as candidates for the factor regulating mRNA levels of OAT1. Our previous longitudinal prospective cohort study, including normal population and CKD patients, revealed that SNP in the promoter region of OAT1 was significantly different between the normal control and CKD groups. The aims of this study are to analyze the association between the rSNPs, which found clinically, and the renal tubular cells injury in vitro and in vivo. In addition, the pathological mechanisms of OAT1 activity on the renal tubular cells damages will be elucidated. Zebra fish animal model and renal tubular culture cell model will be used for the experiments. The results of this study will detail the pathophysilogical genetic basis for the clinical CKD heterogeneity and possibly apply the new direction for the CKD prevention and management.