P. Houillier’s group members conduct researches on the mechanisms and factors controlling ion transport across the tubular epithelium. Understanding these mechanisms and factors is important not only regarding how homeostasis can be preserved under normal conditions but also how the disturbances can explain the various phenotypes encountered in many pathological conditions.
In the recent years, we mainly focused on the renal transport of the divalent cations, calcium and magnesium. The controlled renal transport of these cations is mandatory for the prevention of hypocalcemia and hypomagnesemia, calcium-stone disease and nephrocalcinosis.
The calcium-sensing receptor CaSR is highly expressed in the thick ascending limb. We recently demonstrated that CaSR specifically inhibits calcium reabsorption in the thick ascending limb and is a negative determinant of plasma calcium concentration, independently of its action on parathyroid hormone secretion. Interestingly, the CaSR in the kidney does not affect NaCl reabsorption but alters the paracellular pathway permeability to calcium in the TAL.
Our current projects are
- to understand how the CaSR controls Ca and Mg transport in the renal tubule
- to understand how extracellular Ca affects various renal functions such as NaCl, water and acid transports
- to unravel the pathophysiology of idipopathic (genetic) hypercalciuria.
Immunolocalization of CaSR in the rat kidney.
(A) Immunolocalization of the CaSR protein in the renal cortex and outer medulla. Immunoperoxidase staining in rat kidney sections showed a cytoplasmic and basolateral labeling of tubular cells in the cortex (original magnification, ×200 and ×400) and the inner and outer stripes of the outer medulla (×100). The stained tubules were present in the medullary rays (arrows) and in the juxtaglomerular apparatus (asterisk). Proximal tubules and glomeruli showed no detectable CaSR staining (×1,000). (B) CaSR is expressed in the rat TAL. Shown is double staining with Abs directed against CaSR (red) and Tamm-Horsfall protein (Thp), specifically expressed in the TAL (green). When comparing with tubular segments that stained for Tamm-Horsfall protein, CaSR staining was basolateral (original magnification, ×2,000). (C) CaSR is not detectable in the rat distal convoluted tubule (DCT). Sections of rat kidney double stained for CaSR and the thiazide-sensitive NaCl cotransporter (Ncc) localized in the DCT. Basolateral CaSR staining was interrupted when the tubule showed apical staining for Ncc, thus representing the distal limit for CaSR staining (original magnification, ×1,500). (D) CaSR is not detectable in the rat CCD. Sections of rat kidney double stained for CaSR and aquaporin-2 (Aqp2). In the merged image, tubular segments that stained for aquaporin-2 did not show CaSR staining and vice versa (original magnification, ×1,000).
Picture of a 500 µm rat thick ascending limb (TAL) held by two glass pipettes. The TAL is bathed and perfused with modified Ringer solutions. Drugs cand be added to both sides.
Transepithelial potential difference DPte can be monitored during the experiments.
Pascal Houillier: M.D., University Professor - Hospital Practitioner, Paris Descartes University and Georges Pompidou University Hospital.
Marie-Lucile Figueres: Doctoral student
Renal Proteinase-activated Receptor 2, a New Actor in the Control of Blood Pressure and Plasma Potassium Level. Morla L, Brideau G, Fila M, Crambert G, Cheval L, Houillier P, Ramakrishnan S, Imbert-Teboul M, Doucet A. J Biol Chem. 2013 Apr 5;288(14):10124-31. PMID: 23430254
Alteration of proteoglycan sulfation affects bone growth and remodeling. Gualeni B, de Vernejoul MC, Marty-Morieux C, De Leonardis F, Franchi M, Monti L, Forlino A, Houillier P, Rossi A, Geoffroy V. Bone. 2013 May;54(1):83-91. PMID: 23369989
Haploinsufficiency of the ammonia transporter Rhcg predisposes to chronic acidosis. Rhcg is critical for apical and basolateral ammonia transport in the mouse collecting duct. Bourgeois, S, Bounoure L, Christensen EI, Ramakrishnan SK, Houillier P, Devuyst O, Wagner CA. J Biol Chem, 2013. PMID: 23281477
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M; International Consortium for Blood Pressure (ICBP), Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X. Nat Genet. 2012 Mar 11;44(4):456-60. PMID: 22406640
Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis: Phenotype-Genotype Correlation and Outcome in 32 Patients with CLDN16 or CLDN19 Mutations. Godron A, Harambat J, Boccio V, Mensire A, May A, Rigothier C, Couzi L, Barrou B, Godin M, Chauveau D, Faguer S, Vallet M, Cochat P, Eckart P, Guest G, Guigonis V, Houillier P, Blanchard A, Jeunemaitre X, Vargas-Poussou R. Clin J Am Soc Nephrol. 2012 May;7(5):801-9. PMID: 22422540
More actors in ammonia absorption by the thick ascending limb. Houillier P, Bourgeois S. Am J Physiol Renal Physiol. 2012 Feb;302(3):F293-7. PMID: 22088435
NHE4 is critical for the renal handling of ammonia in rodents. Bourgeois S, Meer LV, Wootla B, Bloch-Faure M, Chambrey R, Shull GE, Gawenis LR, Houillier P. J Clin Invest. 2010 Jun 1;120(6):1895-904. PMID: 20484819
The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. Leviel F, Hübner CA, Houillier P, Morla L, El Moghrabi S, Brideau G, Hatim H, Parker MD, Kurth I, Kougioumtzes A, Sinning A, Pech V, Riemondy KA, Miller RL, Hummler E, Shull GE, Aronson PS, Doucet A, Wall SM, Chambrey R, Eladari D. J Clin Invest. 2010 May 3;120(5):1627-35. PMID: 20389022
Transgenic mice expressing nitroreductase gene under the control of the podocin promoter: a new murine model of inductible glomerular injury. Macary G, Rossert J, Bruneval P, Mandet C, Bélair MF, Houillier P, Van Huyen JP. Virchows Arch. 2010 Mar;456(3):325-37. PMID: 19806361
A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility. Biver S, Belge H, Bourgeois S, Van Vooren P, Nowik M, Scohy S, Houillier P, Szpirer J, Szpirer C, Wagner CA, Devuyst O, Marini AM. Nature. 2008 Nov 20;456(7220):339-43. PMID: 19020613
Exploration of renal tubular functions. Blanchard A, Poussou R, Houillier P. Nephrol Ther. 2009 Feb;5(1):68-83. PMID: 18539554
Exposure to maternal diabetes induces salt-sensitive hypertension and impairs renal function in adult rat offspring. Nehiri T, Duong Van Huyen JP, Viltard M, Fassot C, Heudes D, Freund N, Deschënes G, Houillier P, Bruneval P, Lelièvre-Pégorier M. Diabetes. 2008 Aug;57(8):2167-75. PMID: 18443204
Pitfalls of measuring total blood calcium in patients with CKD. Gauci C, Moranne O, Fouqueray B, de la Faille R, Maruani G, Haymann JP, Jacquot C, Boffa JJ, Flamant M, Rossert J, Urena P, Stengel B, Souberbielle JC, Froissart M, Houillier P; NephroTest Study Group. J Am Soc Nephrol. 2008 Aug;19(8):1592-8. PMID: 18400941
Defective ENaC processing and function in tissue kallikrein-deficient mice. Picard N, Eladari D, El Moghrabi S, Planès C, Bourgeois S, Houillier P, Wang Q, Burnier M, Deschenes G, Knepper MA, Meneton P, Chambrey R. J Biol Chem. 2008 Feb 22;283(8):4602-11. PMID: 18086683