Arterial and renal consequences of partial genetic deficiency in tissue kallikrein activity in humans

Abstract

Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53R-homozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium-high potassium diet to stimulate TK synthesis and a high sodium-low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50-60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people. IntroductionTissue kallikrein (TK), a serine protease synthesized in many organs, cleaves low-and high-molecular-weight kininogens, thus releasing the vasodilator peptides known as kinins (1-4). The kallikrein-kinin system is present in the endothelium and in the smooth muscle of vascular walls (5-7), where locally generated kinins have potent endothelium-mediated vasodilatory and antithrombotic properties through activation of bradykinin B 2 receptors, triggering NO release and other endothelial mediators (1,8,9). TK is also synthesized in large amounts in the kidney connecting tubule and cortical collecting tubule and is released in the urine and the peritubular interstitium (10). The renal kallikrein-kinin system is believed to operate in concert with the renin-angiotensin system to regulate physiologically the distribution of renal blood flow (1,11,12) and the metabolism of water and electrolytes (1). Urinary kallikrein activity (UKLKa) is influenced by hereditary factors (13,14) and by dietary Na + and K + intake (1). Family studies have demonstrated familial aggregation of UKLKa and have suggested that a large part of the observed population variance is attributable to a major gene effect (14). We recently identified a loss-of-function polymorphism in exon 3 of the TK gene. This polymorphism changes an active-site arginine at position 53 to a histidine (R53H), resulting in a substantial loss of kallikrein activity in vitro (15). The 53H allele is found at a frequency of 0.03 in

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Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients

“…A model of kallikrein derived from crystallographic data suggest that arg53 is involved in substrate binding, and individuals with R53H have on average a 50-60% reduction in urinary kallikrein activity. 30 The HapMap project data available in Chinese population exhibit that there are no any frequencies of both rs5516 and rs5515 loci, which indicated it is likely that rs5516 is in strong linkage disequilibrium with known rs5515 (Arg53His) functional variant. YRI population data further support the rs5515 and rs5516 are in complete LD (D 0 ¼ 1).…”

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“…Arteries isolated from mice lacking the kallikrein gene reportedly exhibited significantly reduced flow-induced dilatation compared to controls, suggesting that the KKS in the arterial wall participates in this process (25,168). Moreover, in humans a partial genetic deficiency of TK (R53H) was associated with inward remodeling of the brachial artery that renders it incapable of adapting to a chronic increase in wall shear stress, a form of arterial dysfunction that affects 5% to 7% of Caucasians (13). The effect of ACE inhibitors on local potentiation of kinin-induced vasodilatation appears to be attributable in part to their prevention of bradykinin degradation and increased production of endotheliumderived relaxing factors (EDRFs) such as NO and prostaglandins.…”