Renal organic anion transporters (SLC22 family): expression, regulation, roles in toxicity, and impact on injury and disease

Abstract

Organic solute flux across the basolateral and apical membranes of renal proximal tubule cells is a key process for maintaining systemic homeostasis. It represents an important route for the elimination of metabolic waste products and xenobiotics, as well as for the reclamation of essential compounds. Members of the organic anion transporter (OAT, SLC22) family expressed in proximal tubules comprise one pathway mediating the active renal secretion and reabsorption of organic anions. Many drugs, pesticides, hormones, heavy metal conjugates, components of phytomedicines, and toxins are OAT substrates. Thus, through transporter activity, the kidney can be a target organ for their beneficial or detrimental effects. Detailed knowledge of the OATs expressed in the kidney, their membrane targeting, substrate specificity, and mechanisms of action is essential to understanding organ function and dysfunction. The intracellular processes controlling OAT expression and function, and that can thus modulate kidney transport capacity, are also critical to this understanding. Such knowledge is also providing insight to new areas such as renal transplant research. This review will provide an overview of the OATs for which transport activity has been demonstrated and expression/function in the kidney observed. Examples establishing a role for renal OATs in drug clearance, food/drug-drug interactions, and renal injury and pathology are presented. An update of the current information regarding the regulation of OAT expression is also provided.

Fig. 1

Organic anion transporters of the SLC22 family in human and rodent renal proximal tubule cells. As illustrated, human and rodent orthologs of OAT1/Oat1, OAT2/Oat2, OAT3/Oat3, OAT10/Oat10, and URAT1/Urat1 have been identified. Notable species differences are OAT4 having no identified rodent ortholog and Oat5 and Oat9 having no known human orthologs. Oat8 mRNA has been detected in rodent kidney; however, it is expressed in cortical collecting ducts, not in the proximal tubule; its membrane targeting is not known. The driving forces governing Oat9 function have not been elucidated