Renal kallikrein excretion: role of ethnicity, gender, environment, and genetic risk of hypertension

Song, C. Kay; Martínez, J. Alfredo; Kailasam, MT; Tt, Dao; Wong, CM; Rj, Parmer; O'connor, D. T.

doi:10.1038/sj.jhh.1001047

Cited by 23 publications

(24 citation statements)

References 27 publications

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“…This effect of salt intake on urinary kallikrein excretion was observed in white and black Americans and men and women alike. However, as observed in previous studies, urinary kallikrein excretion was significantly lower in black Americans studied compared with white Americans (Levy et al, 1977;Hughes et al, 1988;Song et al, 2000) and significantly higher in the women studied compared with the men (Hughes et al, 1988;Albano et al, 1994;Song et al, 2000). Numerous previous studies, conducted in predominantly male populations, indicate that urinary kallikrein excretion is decreased in subjects with salt-sensitive or low renin hypertension, although not necessarily in subjects with normal …”

Section: Discussionmentioning

confidence: 46%

Loss of Sodium Modulation of Plasma Kinins in Human Hypertension

Murphey

Eccles²,

Williams³

et al. 2004

J Pharmacol Exp Ther

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We studied the effect of salt intake and hypertension on the systemic kallikrein-kinin system (KKS), as measured by bradykinin (BK) 1-5, a stable circulating bradykinin metabolite, and the tissue KKS, as measured by urinary kallikrein excretion. Venous BK 1-5, urinary kallikrein, and components of the reninangiotensin-aldosterone system were measured in 35 normotensive and 19 hypertensive subjects who were maintained on a high (200 mmol/day) or low (10 mmol/day) salt diet. Salt restriction decreased mean arterial pressure (MAP) (P Ͻ 0.001 overall) and the plasma angiotensin-converting enzyme (P ϭ 0.017) and increased plasma renin activity (P Ͻ 0.001) and serum aldosterone (P Ͻ 0.001). There was an interactive effect of salt intake and hypertension on plasma BK 1-5 (P ϭ 0.043), with BK 1-5 significantly lower during low compared with high salt intake in normotensive (24.7 Ϯ 2.6 versus 34.9 Ϯ 5.6 fmol/ml, P ϭ 0.002) but not hypertensive subjects (30.6 Ϯ 4.6 versus 27.5 Ϯ 2.8 fmol/ml, P ϭ 0.335). In normotensives, the change in plasma BK 1-5 from high to low salt intake correlated with the change in MAP (r ϭ 0.533, P ϭ 0.004). Urinary kallikrein was higher during low compared with high salt intake (P Ͻ 0.001) in both groups. There was no effect of salt intake on urinary BK 1-5. In summary, the systemic and renal KKSs act in tandem to modulate the response to salt intake. The systemic system is activated during high salt intake and counterbalances increased vascular response to pressors. With sodium restriction, the renal system is activated and counterbalances the increased sodium-retaining state induced by activation of the renin-angiotensin-aldosterone system. With hypertension, these modulating effects are diminished or lost, supporting a role for both systems in the development/maintenance of hypertension.

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Section: Discussionmentioning

confidence: 46%

Loss of Sodium Modulation of Plasma Kinins in Human Hypertension

Murphey

Eccles²,

Williams³

et al. 2004

J Pharmacol Exp Ther

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“…45 The kidney may play a crucial role in the development of genetic hypertension, 38 perhaps in response to alterations in renal sympathetic nerve activity, 46 a mechanism which would be congruent with our cardiac autonomic findings (Figure 1). Indeed, we have observed subtle, early changes in glomerular function 47 and vasoactive hormone excretion 48,49 in the still-normotensive offspring of patients with hypertension.…”

Section: Stress Responses and Genetic Risk Of Hypertensionmentioning

confidence: 88%

Cardiovascular haemodynamic response to repeated mental stress in normotensive subjects at genetic risk of hypertension: evidence of enhanced reactivity, blunted adaptation, and delayed recovery

et al. 2003

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To identify unique cardiovascular responses to stressors in a population at genetic risk of hypertension, we studied haemodynamic responses in initial reactivity to, subsequent adaptation to, and final recovery from repeated active mental stress in young, normotensive individuals stratified by hypertension parental history (PH). Two groups (n ¼ 21/group) of normotensive white males underwent stress testing. One group (N+PH) had a hypertensive parent, while the other group (N-PH) did not. Cardiovascular response was measured before, during, and after repeated serial-subtraction math. Initial reactivity was measured as the difference between baseline and initial stress response, subsequent adaptation as the difference in response to repeated trials, and final recovery was assessed by the difference between baseline and postbaseline levels. The influence of PH on reactivity, adaptation, and recovery was assessed by repeated measures ANOVA for stroke volume, cardiac output, pre-ejection period, total peripheral resistance, mean successive heartbeat time difference, blood pressure, and heart rate. Multivariate analysis of variance (MANOVA) determined the effect of PH on overall reactivity, adaptation, and recovery. As compared to the N-PH group, initial reactivity was higher in the N+PH group for cardiac index (Po0.05) and preejection period (Po0.05). Subsequent adaptation in the N+PH group was significantly slower for pre-ejection period (P ¼ 0.03). Finally, the N+PH group showed delayed recovery in heart rate (P ¼ 0.03), diastolic blood pressure (Po0.05), and pre-ejection period (P ¼ 0.007).In conclusion, the heightened reactivity, lack of adaptation, and delayed recovery occur in the sympathetic system of normotensive subjects at genetic risk of hypertension, specifically in beta-adrenergic responses (pre-ejection period). The parasympathetic response (mean successive heartbeat time difference) was not different. Increased cardiac output reactivity in the N+PH group (Po0.05) thus precedes any difference in blood pressure reactivity (Po0.99). Delayed recovery of diastolic blood pressure is also found in the N+PH group (Po0.05), which suggests lower baroreceptor sensitivity. Since delayed recovery in heart rate (P ¼ 0.03), and diastolic blood pressure (Po0.05) occur in N+PH subjects even before the corresponding changes in reactivity (P40.10) or adaptation (P40.07) are seen, these recovery impairments may be among the earliest precursors to the development of essential hypertension in this population. Finally, PH group haemodynamic differences suggest that these traits (reactivity, adaptation, and recovery) may constitute early 'intermediate' phenotypes in the pathogenesis of hypertension.

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“…We studied only white males because gender and ethnic origin are known to influence urinary kallikrein excretion (23,24). We used a new kallikrein-specific enzymatic assay (25) to monitor the level of UKLKa that reflects both the activity and excretion of the renal enzyme.…”

Section: Discussionmentioning

confidence: 99%

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

Azizi

Boutouyrie²,

Bissery³

et al. 2005

J. Clin. Invest.

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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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Renal kallikrein excretion: role of ethnicity, gender, environment, and genetic risk of hypertension

Cited by 23 publications

References 27 publications

Loss of Sodium Modulation of Plasma Kinins in Human Hypertension

Loss of Sodium Modulation of Plasma Kinins in Human Hypertension

Cardiovascular haemodynamic response to repeated mental stress in normotensive subjects at genetic risk of hypertension: evidence of enhanced reactivity, blunted adaptation, and delayed recovery

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

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