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.
1. Hou J†, Renigunta A, Yang J, Waldegger S. Claudin-4 forms paracellular
chloride channel in the kidney and requires claudin-8 for tight junction
localization. Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18010-5.
2. Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J†.
Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a
novel microRNA pathway. EMBO J. 2012 Apr 18;31(8):1999-2012.
3. Hou J†. Lecture: New light on the role of claudins in the kidney.
Organogenesis. 2012 Jan-Mar;8(1):1-9.
4. Hou J†. Regulation of paracellular transport in the distal nephron. Curr Opin
Nephrol Hypertens. 2012 Sep;21(5):547-51.
5. Hou J, Rajagopal M, Yu AS. Claudins and the kidney. Annu Rev Physiol.
6. Gong Y, Hou J†. Claudin-14 underlies Ca⁺⁺-sensing receptor-mediated Ca⁺⁺
metabolism via NFAT-microRNA-based mechanisms. J Am Soc Nephrol. 2014
7. Gong Y, Himmerkus N, Plain A, Bleich M, Hou J†. Epigenetic Regulation of
MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium
Handling. J Am Soc Nephrol. 2014 Jul 28.PMID: 25071082.
8. Gong Y, Yu M, Yang J, Gonzales E, Perez R, Hou M, Tripathi P, Hering-Smith
KS, Hamm LL, Hou J†. The Cap1-claudin-4 regulatory pathway is important for renal
chloride reabsorption and blood pressure regulation. Proc Natl Acad Sci U S A.
2014 Sep 9;111(36):E3766-74.
9. Gong Y, Wang J, Yang J, Gonzales E, Perez R, Hou J†. KLHL3 regulates paracellular chloride transport in the kidney via ubiquitination of claudin-8. Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4340-5. Epub 2015 Mar 23. PubMed PMID: 25831548; PubMed Central PMCID: PMC4394310.
10. Gong Y, Renigunta V, Zhou Y, Wang J, Yang J, Renigunta A, Baker LA, Hou J†. Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization. Mol Biol Cell. 2015.