The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

Carretero, Oscar A.; Yang, Xiao‐Ping; Rhaleb, Nour-Eddine

doi:10.1016/b978-0-7216-0258-5.50110-1

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Tissue 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)(2)(3)(4). The kallikrein-kinin system is present in the endothelium and in the smooth muscle of vascular walls (5)(6)(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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Azizi

¹

,

Boutouyrie²,

Bissery³

et al. 2005

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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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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Azizi¹,

Boutouyrie²,

Bissery³

et al. 2005

View full text Add to dashboard Cite

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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“…Kinins release potent vasodilators, such as prostaglandins (PG), nitric oxide (NO), and endothelial-derived hyperpolarizing factor (EDHF) (3)(4)(5), which influence blood pressure and vessel tone, but they can cause pain and enhance capillary permeability in inflammation as well (3). The beneficial effects of angiotensin I-converting enzyme (ACE) (18,40), or kininase II are attributed at least in part to prolongation of the half-life of bradykinin (BK) (6)(7)(8)(20)(21)(22) and potentiation of its effects on the B 2 receptor (15,(33)(34)(35). Although plasma kininogen is the primary substrate of kallikreins, these serine proteases can cleave other proteins as well, such as Factor XII, the activator of prokallikrein (12,41,42).…”

Section: Introductionmentioning

confidence: 99%

Kallikrein activates bradykinin B₂ receptors in absence of kininogen

Biyashev

¹

,

Tan

²

,

Chen

³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Kallikreins cleave plasma kininogens to release the bioactive peptides bradykinin (BK) or kallidin (Lys-BK). These peptides then activate widely disseminated B 2 receptors with consequences that may be either noxious or beneficial. We used cultured cells to show that kallikrein can bypass kinin release to activate BK B 2 receptors directly. To exclude intermediate kinin release or kininogen uptake from the culture medium, we cultured and maintained cells in medium entirely free of animal proteins. We compared the responses of stably transfected CHO cells that express human B 2 receptors (CHO-B 2 ) and cells that co-express angiotensin I-converting enzyme (ACE) as well (CHO AB). We found that BK (1 nM or more) and tissue kallikrein (1-10 nM) both significantly increased release of arachidonic acid beyond unstimulated or baseline levels. An enzyme-linked immunoassay for kinin established that kallikrein did not release a kinin from CHO cells. We confirmed the absence of kininogen mRNA with RT-PCR to rule out kininogen synthesis by CHO cells. Next, we tested an ACE inhibitor for enhanced BK receptor activation in the absence of kinin release and synthesized an ACE-resistant BK analogue as a control for these experiments. Enalaprilat (1μM) potentiated kallikrein (100 nM) in CHO AB cells but was ineffective in CHO B 2 cells that do not bear ACE. We concluded that kallikrein activated B 2 receptors without releasing a kinin. Furthermore, inhibition of ACE enhanced the receptor activation by kallikrein, an action that may contribute to the manifold therapeutic effects of ACE inhibitors.

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The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

Cited by 18 publications

References 223 publications

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

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

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

Kallikrein activates bradykinin B₂ receptors in absence of kininogen

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The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

Cited by 18 publications

References 223 publications

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

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

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

Kallikrein activates bradykinin B2 receptors in absence of kininogen

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Kallikrein activates bradykinin B₂ receptors in absence of kininogen