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Tissue Kallikrein–Deficient Mice Display a Defect in Renal Tubular Calcium Absorption

Nicolas Picard^*, Monique Van Abel, Christelle Campone^*,,, Michelle Seiler^||, May Bloch-Faure^*, Joost G.J. Hoenderop, Johannes Loffing^||, Pierre Meneton^*, René J.M. Bindels, Michel Paillard^*,,, François Alhenc-Gelas^* and Pascal Houillier^*,,

^* INSERM, Unité 652, and Institut Fédératif de Recherche 58, Paris, France; Department of Physiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; Université Paris-Descartes, Faculté de Médecine, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Département de Physiologie, Paris, France; and ^|| Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Address correspondence to: Dr. Pascal Houillier, Département de Physiologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. Phone: +33-1-5609-3974; Fax: +33-1-5609-3995; E-mail:pascal.houillier{at}egp.ap-hop-paris.fr

Received for publication November 9, 2004. Accepted for publication September 6, 2005.

Renal tubular calcium (RTCa) transport is one of the main factors that determine serum Ca concentration and urinary Ca excretion. The distal convoluted and connecting tubules reabsorb a significant fraction (10%) of filtered Ca. These tubule segments also synthesize in large abundance tissue kallikrein (TK), a major kinin-forming enzyme. Tested was the hypothesis that TK and kinins are involved in controlling RTCa transport by studying TK (TK–/–) or kinin B2 receptor (B2–/–)-deficient mice on different Ca diets. On a 0.9% wt/wt Ca diet, 129Sv or C57Bl/6 TK–/– mice excreted significantly more Ca in urine than their wild-type (WT) littermates. There was no difference between TK–/– and WT mice for plasma concentrations of Ca, Mg, creatinine, parathyroid hormone, or 1,25-dihydroxyvitamin D. On a low Ca (LCa) diet (0.01% wt/wt), urinary Ca excretion decreased in both TK–/– and WT mice but still remained higher in TK–/– mice compared with WT. The plasma Ca concentration was unchanged in C57Bl/6 TK–/– mice but decreased significantly in 129Sv TK–/– mice. Taken together, these data demonstrate that TK deficiency led to impaired RTCa absorption. On the LCa diet, renal TK gene expression doubled in WT mice. No change in urinary Ca excretion was observed in B2–/– mice, even after treatment with a kinin B1-receptor antagonist, and these mice adapted normally to the LCa diet. TK deficiency had no effect on the renal abundance of distal Ca transporter mRNA. These data suggest that TK may be a physiologic regulator of RTCa transport, acting through a non–kinin-mediated mechanism.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673