The central research focus of our laboratory is the study of transport processes expressed in the kidney involved in clearing the body of toxic chemicals. Every day we are typically exposed to several grams of "xenobiotic" compounds, generally from the foods we eat and from the pharmaceutical agents we ingest. These chemicals represent the best efforts of plants to kill (or at least irritate) the animals that eat them; or, in the case of pharmaceutical agents, our best efforts to modify plant derived products to meet our therapeutic needs. Most (arguably, all) of these compounds are toxic if taken in high enough quantities, and often toxicity arises from exposure to very small amounts of these xenobiotic compounds. A principal strategy of animals to deal with plant "chemical warfare" is to use cellular transport processes to keep the toxic agents at bay. These transport processes are generally found in so-called 'barrier epithelial," i.e., the intestine (to prevent the toxins from entering the body); the liver and the kidney (to clear the body of these toxins should they gain access).
The renal proximal tubule is the major site for secretion of a vast array of compounds that can generally be placed into one of two broad chemical categories: organic cations or organic anions, i.e., organic molecules that, at physiological pH carry a net positive or a net negative charge, respectively; collectively these compounds are organic electrolytes (OEs). The process of renal secretion reflects the concerted activity of transport processes expressed within the basolateral and luminal membranes of proximal tubule cells. Until comparatively recently, the molecular basis of the basolateral and luminal steps in renal OE secretion were poorly understood. We now know the 'circles and arrows' depicted in this simple scheme actually consist of a complex suite of discrete transport proteins. The figure to the right shows the current view of the organization of transport proteins involved with the secretion of organic cations; the profile of organic anion transporters is equally Byzantine.Our work is focused on understanding the molecular and cellular physiology of the transporters that handle organic cations (OCs) and organic anions (OAs) in renal proximal tubule. Currently funded projects include:
1. Molecular organization of renal organic cation transport
2. Molecular organization of renal organic anion transport
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Pelis, R.M., W.M. Suhre, and S.H. Wright. 2006. Functional influence of N-glycosylation in OCT2-mediated tetraethylammonium transport. American Journal of Physiology (Renal Physiology) 290: F1118-F1126.
Groves, C.E., W.B. Suhre, N.J. Cherrington, and S.H. Wright. 2006. Sex differences in the mRNA, protein and functional expression of Oat1, Oat3 and Oct2 in rabbit renal proximal tubules. Journal of Pharmacology and Experimental Therapeutics 316: 743-752.
Aavula, B.R., M.A. Ali, D. Bednarczyk, S.H. Wright, and E.A. Mash. 2006. Synthesis and fluorescence of n,n,n-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium iodide, a ph-insensitive reporter of organic cation transport. Synthetic Communications 36: 701-705.
Zhang, X., N.V. Shirahattiand, D. Mahadevan, and S.H. Wright. 2005. A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2). Journal of Biological Chemistry 280: 34813-34822.
Soodvilai, S., S.H. Wright, W.H. Dantzler, and V. Chatsudthipong. 2005. Involvement of tyrosine kinase and PI3K in the regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules. American Journal of Physiology (Renal Physiology) 289: F1057-F1064.
Suhre, W.M., S. Ekins, C. Chang, P.W. Swaan, and S.H. Wright. 2005. Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters, hOCT2 and rbOCT2. Molecular Pharmacology 67: 1067-1077.
Zhang, X., C.E. Groves, A. Bahn, W.M. Barendt, M.D. Prado. M. Rödiger, V. Chatsudthipong, G. Burckhardt, and S.H. Wright. 2004. Relative contribution of OAT and OCT transporters to organic electrolyte transport in rabbit proximal tubule. American Journal of Physiology (Renal Physiology) 287: F999-1010.
Soodvilai, S., V. Chatsudthipong, K.K. Evans, S.H. Wright, and W.H. Dantzler. 2004. Acute regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules. American Journal of Physiology (Renal Physiology) 287: F1021-1029.
Wright, S.H., K.K. Evans, X. Zhang, N.J. Cherrington, D.S. Sitar, and W.H. Dantzler. 2004. Functional map of TEA transport activity in isolated rabbit renal proximal tubules. American Journal of Physiology (Renal Physiology) 287: F442-451.
Wright, S.H., and W.H. Dantzler. 2004. Molecular and cellular physiology of renal organic cation and anion transport. Physiological Review 84: 987-1049.
