Tong Wang MD

Professor of Cellular and Molecular Physiology

Research Interests

Kidney tubule transport; Electrolyte and acid-base balance; Transgenic animal models and human disease

Current Projects

Studying flow-activated salt, water and bicarbonate transport in kidney proximal tubules and flow-induced changes in ion transporter function and regulation, to explore the mechanism of glomerulotubular balance (GTB). Briefly, GTB is a critical aspect of proximal tubule transport that maintains nearly proportional change in reabsorption of Na+, HCO3-, Cl- and water with variations in glomerular filtration (GFR). GTB acts to prevent renal solute loss following a GFR increase, and also allows preservation of adequate distal sodium delivery in times of low GFR, thus limiting compromise of distal nephron acid and potassium excretion. We are hoping to determine what the flow sensor is in the proximal tubule; how tubule transport is regulated by flow; how the flow signal can be transduced to the membrane transporters; and how membrane transporter activity is activated by increased tubular flow.
Studying the structure and function of renal potassium channels in the regulation of salt, water and acid-base balance to understand the mechanism of Bartter's syndrome in humans. Briefly, the renal outer medullary potassium channel (ROMK) is an ATP-sensitive inward-rectifier potassium channel highly expressed in the cortical and medullary thick ascending limbs (TAL), connecting segment (CNT) and cortical collecting duct (CCD) in the mammalian kidney, where it serves to recycle K+ across the apical membrane in TAL and secrete K+ in the CNT and CCD. ROMK channel mutations cause a type II Bartter's syndrome with salt wasting and dehydration, and ROMK knockout mice have a similar phenotype to Bartter's syndrome in humans. We have used the ROMK knockout mice to study electrolyte and acid-base transport along the nephron to understand TAL function under physiological conditions and to explore the compensatory mechanisms of salt and water transport, acid-base balance and blood pressure regulation under the conditions of TAL dysfunction.

Core activities:
  • Integrated Kidney Function Core: Support the departmental Program Project to study ion transport mechanisms in kidney tubules by using different transgenic animal models.
  • Renal Physiology Core: Provide services to the George M O'Brien Kidney Center at Yale for the study of renal functions in small animal models and to support PI's projects worldwide.

Research Summary

Our major research focus is to characterize the cellular and molecular mechanisms underlying regulation of electrolyte transport in kidney tubules, acid-base balance and general kidney functions. In particular, we use genetically manipulated animal models to conduct both in vivo and in vitro microperfusion of kidney tubules to characterize the functional roles of ion transporters, pumps and channels in physiology and transport lesions. We are one of the few labs in the world that is able to conduct both in vivo and in vitro microperfusion of kidney tubules from single nephrons of mouse kidney.

Our lab is the core Laboratory of Integrated Kidney Function in the Department of Cellular & Molecular Physiology and also the Renal Physiology Core of the George M O'Brien Kidney Center at Yale University. We have a large number of collaborations both inside and outside of Yale University and provide training and services to examine phenotypes of blood pressure, GFR, electrolyte excretion and acid-base parameters in transgenic and knockout animal models. Our expertise is the use of transgenic animal models and the examination of their phenotypes in blood pressure, renal functions, kidney tubule transport and acid-base balance.

Extensive Research Description

Our major research interests are investigating the cellular and molecular mechanisms and regulation of electrolyte transport in kidney tubules, in particular using genetically manipulated animal models to study their phenotypes. Phenotypes of mutant or knockout animals will provide information on the physiology or pathophysiology of the target proteins. By using transgenic animal models, we can mimic clinical diseases for a better understanding of the mechanisms and treatments of these diseases in humans.
The major experimental techniques used in this lab include: metabolic studies; renal clearance in rats and mice; microperfusion of the proximal tubule, loop of Henle and distal tubules in vivo; microperfusion of kidney proximal and collecting tubules in vitro in rats and mice; measurement of cell pH; and analysis of Na+, Cl-, K+, HCO3- concentrations in nanoliter samples. Using these methods, we have studied kidney tubule functions and tubule transport in many knockout and transgenic animal models such as NHE3 (the predominant isoform responsible for apical membrane Na+/H+exchange, which mediates 50 to 60% of Na+ and HCO3- absorption in the kidney proximal tubule). We have also studied eNOS, nNOS, iNOS (endothelial, neuronal and inducible nitric oxide synthases, a family of enzymes that synthesizes NO from L-arginine in mammalian tissue and is expressed in the kidney); CEFX (SLC26A6, PAT1, a Cl--anion exchanger located in the brush border of the proximal tubule, which mediates the principal component of the Cl--base exchange), PDZK1 (a PDZ-binding domain containing protein identified in kidney, pancreas, liver, gastrointestinal tract, and adrenal cortex, which is localized exclusively in the brush border of the proximal tubule and may be capable of interaction with numerous renal proteins including NHE3 and CEFX). Our research also covers NHERF-1 (NHE regulatory factor, which interacts with cAMP-mediated NHE3 activity); pendrin (the protein product of the PDS gene [SLC26A4], with functions in several different anion exchange modes including chloride/formate exchange), and ROMK knockout mice.


Selected Publications

  • Du, Z., Wan, L., Yan, Q., Weinbaum, S., Weinstein, AM and Wang, T. Regulation of Glomerulotubular Balance II: Impact of Angiotensin II on Flow-Dependent Transport. AJP Renal, 303(11): F1507-16, 2012.
  • Du, Z., Yan, Q., Wan, L., Weinbaum, S., Weinstein, AM and Wang, T. Regulation of Glomerulotubular Balance I: Impact of Dopamine on Flow-Dependent Transport. AJP Renal, 303(3): F386-95, 2012.
  • Wang, T. Renal outer medullary potassium channel knockout models reveal thick ascending limb function and dysfunction. Clin Exp Nephrol., 16(1):49-54, 2012.
  • Wade JB, Fang L, Coleman RA, Liu J, Grimm PR, Wang T, Welling PA. Differential Regulation of ROMK (Kir1.1) in Distal Nephron Segments by Dietary Potassium. Am J Physiol Renal Physiol. 300(6): F1385-1393, 2011
  • Lin Z, Jin S, Duan X, Wang T, Martini S, Hulamm P, Cha B, Hubbard A, Donowitz M, Guggino SE. Chloride channel (Clc)-5 is necessary for exocytic trafficking of Na+/H+ exchanger 3 (NHE3). J Biol Chem. 286(26): 22833-45, 2011.
  • Gotoh N, Yan Q, Du Z, Biemesderfer D, Kashgarian M, Mooseker MS, Wang T. Altered renal proximal tubular endocytosis and histology in mice lacking myosin-VI. Cytoskeleton, 67(3):178-9, 2010.
  • Weinbaum S, Duan Y, Satlin LM, Wang T, Weinstein AM. Mechanotransduction in the renal tubule. AJP Renal, 299:F1220-F1236, 2010.
  • Pluznick JL, Zou DJ, Zhang X, Yan Q, Rodriguez-Gil DJ, Eisner C, Wells E, Greer CA, Wang T, Firestein S, Schnermann J, Caplan MJ. Functional Expression of the Olfactory Signaling System in the Kidney. PNAS, 106(6): 2059-64, 2009.
  • Krendel M, Kim SV, Willinger T, Wang T, Kashgarian M, Flavell RA, Mooseker MS. Disruption of Myosin 1e promotes podocyte injury. JASN, 20:86-94, 2009.
  • Dvoryanchikov G, Sinclair MS, Perea-Martinez I, Wang T, Chaudhari N. Inward rectifier channel, ROMK, is localized to the apical tips of glial-like cells in mouse taste buds. J Comp Neurol, 517:1-14, 2009.

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