Epithelia permit selective and regulated flux from apical to basolateral surfaces by transcellular passage through cells or paracellular flux between cells. Claudins are the key components of the paracellular pathway. Defects in claudin function result in a broad range of renal diseases, including hypomagnesemia, hypercalciuria, hypochloremia and salt-sensitive hypertension. Nevertheless, the roles of claudins in renal handling of electrolytes are largely elusive. Our lab develops transgenic siRNA mouse models to manipulate claudin expression in vivo and study their functions in paracellular transport of electrolytes. Our research interests are:
(1) Study paracellular reabsorption of magnesium in the Henle’s loop. The renal reabsorption of Mg2+ is primarily handled by the thick ascending limb (TAL) of Henle’s loop through the paracellular pathway. Its major constituents are claudin-16 and claudin-19. We have developed claudin-16 knockdown (KD) and claudin-19 KD mouse lines. Claudin-16 KD animals show chronic renal wasting of magnesium and calcium, developing nephrocalcinosis comparable to human FHHNC phenotypes. Future studies will show if the interaction between claudin-16 and claudin-19 is required for normal function of the TAL.
(2) Study distal paracellular reabsorption of chloride. The paracellular reabsorption of Cl- in the collecting duct is important for renal handling of salt and managing blood pressure. Claudin-4 and claudin-8 are key molecular components of this pathway. To elucidate their functions, we will generate claudin-4 KD and claudin-8 KD mice and analyze them for defects in chloride homeostasis.
(3) Study proximal paracellular salt reabsorption. The paracellular pathway in the proximal tubule is critical for salt reabsorption owing to its leaky tight junction and consists of claudin-2 and claudin-18. Using tissue-specific siRNA transgenic strategy, we will generate claudin-2 KD and claudin-18 KD in the proximal tubule of mouse kidney. These animals will be important tools to understand the paracellular transport function of the proximal tubule