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

Abstract

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.

The Role of Bradykinin System in Type 2 Diabetes

“…This observation might be a reflection on the utilization of kininogen to form BK, a proinflammatory agent as previously reported [35,36]. BK1R and BK2R antagonists may normalize the diabetic state in experimentally induced diabetes in mice [37]. Thus, BK antagonist may be targeted for use in diabetic disorders.…”

Recombinant adeno-associated virus-mediated human kallikrein gene therapy prevents high-salt diet-induced hypertension without effect on basal blood pressure1

“…In these mice, the lack of B2 receptor from early development did not alter the maturation of blood pressure under conditions of normal sodium intake [25] . Interestingly, our results showed that human tissue kallikrein gene delivery in normal SD rats had no effect on the excretion of natrium from the kidney under normal sodium intake, although it has been known that renal KKS is involved in the excretion of natrium in the kidney [15] . The renal KKS is composed of renal kallikrein, its inhibitor (kallistatin), low molecular weight kininogen, 2 tubular-specific kinases, and kinin receptors.…”

“…Renal kallikrein is synthesized in the connecting tubule cells in the distal nephron, and is involved in the homeostasis of sodium and water balance in the kidney. Its attenuation is suggested as a possible etiological factor in salt-sensitive hypertension [15,16] . Our previous studies have demonstrated that rAAV-HK delivery attenuates the increased blood pressure induced by fructose or streptozotocin in conjunction with a high-fat diet and ameliorates organ injury [17] .…”

Activation of the Bradykinin System by Angiotensin-Converting Enzyme Inhibitors

“…There is ample evidence documenting the role of BK in the pathogenesis of hypertension (9)(10). The pharmacological actions of BK in regulation of systemic BP are vasodilation in most areas of circulation, reduction in total peripheral vascular resistance and regulation of sodium excretion from the kidney (11).…”