Renal organic anion transport: A comparative and cellular perspective

A major system for net transepithelial secretion of a wide range of hydrophobic organic anions (OAs) exists in the proximal renal tubules of almost all vertebrates. This process involves transport into the cells against an electrochemical gradient at the basolateral membrane and movement from the cells into the lumen down an electrochemical gradient. Transport into the cells at the basolateral membrane, which is the dominant, rate-limiting step, is a tertiary active transport process, the final step which involves countertransport of the OA into the cells against its electrochemical gradient in exchange for α-ketoglutarate moving out of the cells down its electrochemical gradient. The outwardly directed gradient for α-ketoglutarate is maintained by metabolism (∼40%) and by transport into the cells across both the basolateral and luminal membranes by separate sodium-dicarboxylate cotransporters (∼60%). The inwardly directed sodium gradient driving α-ketoglutarate uptake is maintained by the basolateral Na⁺-K⁺-ATPase, the primary energy-requiring transport step in the total tertiary process. The basolateral OA/α-ketoglutarate exchange process now appears to be physiologically regulated by several factors in mammalian tubules, including peptide hormones (e.g., bradykinin) and the autonomic nervous system acting via protein kinase C (PKC) pathways and epidermal growth factor (EGF) working via the mitogen-activated protein kinase (MAPK) pathway.