Renal Secretory Systems
John B. Pritchard, Ph.D.
Principal Investigator and Chief,
Laboratory of Pharmacology
Tel (919) 541-4054
Fax (919) 541-5737
firstname.lastname@example.org P.O. Box 12233
Mail Drop F1-03
Research Triangle Park, North Carolina 27709
The toxicity of foreign chemicals is determined by dose and duration of exposure at critical sites within the body. In concert with metabolic oxidation, excretion of xenobiotics, drugs, and their metabolism is critical for protection against toxic effects. Two active transport systems mediate their renal excretion, the organic anion (OA) and organic cation (OC) secretory systems. Both are notable for their effectiveness, i.e., their ability to clear the blood of certain substrates in a single pass through the kidney, and their ability to handle a very wide range of substrates. The Renal Pharmacology Group’s focus has been on understanding how this remarkable capacity is achieved.
Prior work by the group utilizing isolated membrane vesicles led to a mechanistic understanding of the rate limiting step in renal secretion of OA, basolateral uptake from the blood into the cells of the proximal tubule (Figure 1). This step is driven via a unique tertiary coupling to metabolic energy. ATP is hydrolyzed by the Na+-pump to generate an out>in Na+-gradient (Step 1). In turn, the Na+-gradient drives Na+/α-ketoglutarate (αKG) cotransport (Step 2) and sustains an in>out gradient for αKG. The αKG-gradient drives OA uptake against its electrochemical gradient via αKG/OA exchange (Step 3). The group subsequently cloned both rat and human forms of this exchanger (Figure 2).
Recent work has focused on three aspects of organic anion secretion:
Additional studies have shown that the same transporters operate in the choroid plexus, but that both OA and OC transport are in the opposite direction, i.e., from cerebrospinal fluid (CSF) to the blood, rather than from the blood as in kidney. Interestingly, OAT1 and OCT2 are expressed on the apical, or CFS-facing, membrane in choroid plexus as predicted by the direction of net transport. Figure 4 illustrates these data, showing the distribution a cytoplasmic GFP construct—which is found throughout the cell and nucleus (Panel A), and of the GFP/OAT1 protein—which is expressed in the apical (CSF facing) membrane (Panels B and D). Panel C is a transmitted light image of the same tissue seen in the adjacent fluorescence image (D).
Major areas of research:
John B. Pritchard, Ph.D., heads the Renal Pharmacology Group, but he has several additional roles within NIEHS. He is Chief of the Laboratory of Pharmacology, Acting Chief of the Laboratory of Molecular Toxicology, and Director of the Environmental Toxicology Program. He received his Ph.D. in physiology from Harvard University in 1970. He has published ~100 peer-reviewed articles in leading biomedical journals, as well as more than 15 book chapters. He served as a Associate Professor of Physiology at the Medical University of South Carolina before joining NIEHS in 1976. He has also served as Associate Editor of the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology since 2001.