Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

Katori, Makoto; Murakami, Masataka

doi:10.1254/jjp.70.95

Cited by 48 publications

(38 citation statements)

References 184 publications

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“…Thus, the normally acting renal kallikrein-kinin system plays the role of a safety valve for excess sodium intake (10,161,162) and the reduced function of the renal kallikrein-kinin system may lead to salt-sensitive hypertension after a high salt intake. Accordingly, enhancement of the natural activity of the renal kallikrein-kinin system must suppress the salt-sensitive hypertension or other hypertensions.…”

Section: Potassium and Urinary Kallikreinmentioning

confidence: 99%

A Missing Link Between a High Salt Intake and Blood Pressure Increase

Katori

Murakami

2006

J Pharmacol Sci

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Abstract. It is widely accepted that a high sodium intake triggers blood pressure rise. However, only one-third of the normotensive subjects were reported to show salt-sensitivity in their blood pressure. Many factors have been proposed as causes of salt-sensitive hypertension, but none of them provides a satisfactory explanation. We propose, on the basis of accumulated data, that the reduced activity of the kallikrein-kinin system in the kidney may provide this link. Renal kallikrein is secreted by the distal connecting tubular cells and all kallikrein-kinin system components are distributed along the collecting ducts in the distal nephron. Bradykinin generated is immediately destroyed by carboxypeptidase Y-like exopeptidase and neutral endopeptidase, both quite independent from the kininases in plasma, such as angiotensin converting enzyme. The salt-sensitivity of the blood pressure depends largely upon ethnicity and potassium intake. Interestingly, potassium and ATP-sensitive potassium (K ATP ) channel blockers accelerate renal kallikrein secretion and suppress blood pressure rises in animal hypertension models. Measurement of urinary kallikrein may become necessary in salt-sensitive normotensive and hypertensive subjects. Furthermore, pharmaceutical development of renal kallikrein releasers, such as K ATP channel blockers, and renal kininase inhibitors, such as ebelactone B, may lead to the development of novel antihypertensive drugs.

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Section: Potassium and Urinary Kallikreinmentioning

confidence: 99%

A Missing Link Between a High Salt Intake and Blood Pressure Increase

Katori

Murakami

2006

J Pharmacol Sci

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“…The findings indicate that the expression of tissue kallikreinkinin system components are crucially important for cardiovascular and renal function such as the kidney, heart, brain and aorta. 7,[19][20][21] Gene therapy for hypertension is a viable strategy. [1][2][3] The application of kallikrein gene therapy to reduce blood pressure has been tested in several hypertensive rat models, and the results showed that the injection of various kallikrein gene constructs with adenovirus or plasmids caused a significant reduction in systemic blood pressure in SHRs, one-clip Goldblatt hypertensive rats and Dahl-salt-sensitive hypertensive rats.…”

Section: Introductionmentioning

confidence: 99%

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Wang

Zhao

et al. 2004

Gene Ther

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Gene therapy of hypertension requires long-term expression of a therapeutic gene to achieve stable reduction of blood pressure. Human tissue kallikrein (HK) cleaves kininogen to produce a potent vasoactive peptide kinin, which plays an important role in the regulation of the cardiovascular and renal functions. In the present study, we have delivered human kallikrein cDNA with an rAAV vector to explore the potential therapeutic effects of kallikrein on hypertension and related secondary complications. A single tail vein injection of the rAAV-HK vector into the adult spontaneously hypertensive rats resulted in a significant reduction (12.072.55 mmHg, Po0.05, n ¼ 6, ANOVA) of the systolic blood pressure from 2 weeks after vector injection, when compared with the control rAAV-lacZ vector-injected rats. Weekly blood pressure monitoring showed stable hypertension-reduction effect throughout the course of the 20-week experiments. In addition, total urine microalbumin contents decreased as a result of rAAV-HK treatment. Histological analysis of various tissues showed remarkable amelioration of cardiovascular hypertrophy, renal injury and collagen depositions in the rAAV-treated group. Finally, persistent expression of the transgene product HK was confirmed by the enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. We conclude that rAAV-mediated HK delivery rendered a long-term and stable reduction of hypertension and protected against renal injury, cardiac remodeling in the spontaneously hypertensive rat model. Further studies are warranted for the development of a gene therapy strategy for human hypertension.

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“…Although the detection of these patients is due to their severe abnormality in surface-activated intrinsic coagulation, fibrinolytic and kiningenerating pathways, these patients have little or no bleeding abnormality (6,7). However, studies in experimental animals provide evidence for an important role for kinin peptides in the regulation of blood pressure and sodium homeostasis, and in contributing to inflammatory processes (8)(9)(10)(11). The B 2 receptor gene knockout mouse is hypertensive with cardiac hypertrophy (8).…”

Section: Introductionmentioning

confidence: 99%

“…The B 2 receptor gene knockout mouse is hypertensive with cardiac hypertrophy (8). Both the B 2 receptor gene knockout mouse and the kininogen-deficient Brown-Norway Katholiek rat strain show increased sensitivity to the pressor effects of increased dietary salt, mineralocorticoid administration, and angiotensin II (Ang II) infusion, and an impairment of the cardioprotective effects of preconditioning (8)(9)(10)(11). In addition, the BrownNorway Katholiek rat strain shows a reduced response to inflammatory stimuli (10).…”

Section: Introductionmentioning

confidence: 99%

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

2000

Braz J Med Biol Res

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The kallikrein-kinin system is complex, with several bioactive peptides that are formed in many different compartments. Kinin peptides are implicated in many physiological and pathological processes including the regulation of blood pressure and sodium homeostasis, inflammatory processes, and the cardioprotective effects of preconditioning. We established a methodology for the measurement of individual kinin peptides in order to study the function of the kallikreinkinin system. The levels of kinin peptides in tissues were higher than in blood, confirming the primary tissue localization of the kallikreinkinin system. Moreover, the separate measurement of bradykinin and kallidin peptides in man demonstrated the differential regulation of the plasma and tissue kallikrein-kinin systems, respectively. Kinin peptide levels were increased in the heart of rats with myocardial infarction, in tissues of diabetic and spontaneously hypertensive rats, and in urine of patients with interstitial cystitis, suggesting a role for kinin peptides in the pathogenesis of these conditions. By contrast, blood levels of kallidin, but not bradykinin, peptides were suppressed in patients with severe cardiac failure, suggesting that the activity of the tissue kallikrein-kinin system may be suppressed in this condition. Both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors increased bradykinin peptide levels. ACE and NEP inhibitors had different effects on kinin peptide levels in blood, urine, and tissues, which may be accounted for by the differential contributions of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs. Measurement of the levels of individual kinin peptides has given important information about the operation of the kallikrein-kinin system and its role in physiology and disease states.

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Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

Cited by 48 publications

References 184 publications

A Missing Link Between a High Salt Intake and Blood Pressure Increase

A Missing Link Between a High Salt Intake and Blood Pressure Increase

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

Towards understanding the kallikrein-kinin system: insights from measurement of kinin peptides

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