Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters.
The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liver-derived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.
Department of Medicine, Department of Pediatrics, Department of Cell & Molecular Medicine, snigam@ucsd.edu.
Sanjay K
SK
Nigam
Department of Medicine.
Wei
W
Wu
Department of Pediatrics.
Kevin T
KT
Bush
Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Melanie P
MP
Hoenig
Division of Nephrology-Hypertension, and Veterans Affairs San Diego Healthcare System, San Diego, California; and.
Roland C
RC
Blantz
Division of Family & Preventative Medicine, University of California-San Diego, La Jolla, California;
Vibha
V
Bhatnagar
D001692:Biological Transport; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000145:classification / Q000502:physiology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015398:Signal Transduction; D014511:Uremia
D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations
ATP-Binding Cassette Transporters; Acute Kidney Injury; Anti-Bacterial Agents; Cations; Chronic; Diuretics; Organic Anion Transporters; Renal Insufficiency; drug transporter; nephrotoxicity; renal physiology