Tong Wang, MD

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. 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.