Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity

Rola Slim, Florence Torremocha, Thierry Moreau, Anne Pizard, Steven Hunt, Albert Vuagnat, Gordon H. Williams, Francis Gauthier, Xavier Jeunemaitre, François Alhenc-Gelas

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Kallikrein is synthesized in the distal tubules and produces kinins, which are involved in the regulation of vascular tone in the kidney. Urinary kallikrein activity has been reported to be partly inherited and to be reduced in essential hypertension. In a systematic search for molecular variants of the human kallikrein gene, nine single-nucleotide polymorphisms were identified. Five of those polymorphisms, including two nonsynonymous substitutions in exon 3, i.e., Arg53His (allelic frequency in Caucasian subjects, 0.03) and Gln121Glu (allelic frequency, 0.33), were studied in a normotensive group and two independent hypertensive groups for which 24-h urinary kallikrein activity had been measured. A significant decrease in urinary kallikrein activity was observed for the subjects who were heterozygous for the Arg53His polymorphism, compared with the other subjects. This finding was consistent in the two hypertensive groups and was observed with several kallikrein enzymatic assays. The Gln121Glu polymorphism and the other polymorphisms were not associated with changes in urinary kallikrein activity. None of the polymorphisms was associated with hypertension. Recombinant kallikrein variants were synthesized and enzymatically characterized, using native kininogen and kininogen-derived synthetic peptide substrates. No important effect was observed after Gln121 mutation, but there was a major decrease in enzyme activity when Arg53 was replaced by histidine. A model of kallikrein derived from crystallographic data suggested that Arg53 can affect substrate binding. The identification of a subset of subjects with genetically reduced kallikrein activity as a result of an amino acid mutation could facilitate analysis of the role of the kallikrein-kinin system in renal and vascular diseases.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalJournal of the American Society of Nephrology
Volume13
Issue number4
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Tissue Kallikreins
Kallikreins
Kininogens
Genes
Kallikrein-Kinin System
Kidney
Kinins
Mutation
Enzyme Assays
Vascular Diseases
Histidine
Single Nucleotide Polymorphism
Blood Vessels
Exons
Hypertension
Amino Acids
Peptides
Enzymes

ASJC Scopus subject areas

  • Nephrology

Cite this

Slim, R., Torremocha, F., Moreau, T., Pizard, A., Hunt, S., Vuagnat, A., ... Alhenc-Gelas, F. (2002). Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. Journal of the American Society of Nephrology, 13(4), 968-976.

Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. / Slim, Rola; Torremocha, Florence; Moreau, Thierry; Pizard, Anne; Hunt, Steven; Vuagnat, Albert; Williams, Gordon H.; Gauthier, Francis; Jeunemaitre, Xavier; Alhenc-Gelas, François.

In: Journal of the American Society of Nephrology, Vol. 13, No. 4, 2002, p. 968-976.

Research output: Contribution to journalArticle

Slim, R, Torremocha, F, Moreau, T, Pizard, A, Hunt, S, Vuagnat, A, Williams, GH, Gauthier, F, Jeunemaitre, X & Alhenc-Gelas, F 2002, 'Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity', Journal of the American Society of Nephrology, vol. 13, no. 4, pp. 968-976.
Slim, Rola ; Torremocha, Florence ; Moreau, Thierry ; Pizard, Anne ; Hunt, Steven ; Vuagnat, Albert ; Williams, Gordon H. ; Gauthier, Francis ; Jeunemaitre, Xavier ; Alhenc-Gelas, François. / Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. In: Journal of the American Society of Nephrology. 2002 ; Vol. 13, No. 4. pp. 968-976.
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AU - Hunt, Steven

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