Renal Kallikrein Secretion Research Articles

A Proposal----The Renal Kallikrein-Kinin System as a Compensating System for Salt Accumulation after Excess Salt Intake

Terrestrial mammals, like human, must reserve water and NaCl to counter the effects of dry-environments. Their kidneys need to reabsorb as much water and sodium as possible along the proximal tubules and collecting duct. Thus, excess sodium intake tends to sodium accumulation in the body. The renal (tissue) kallikrein-kinin system (KKS) exists to prevent excessive sodium reabsorption. Renal kallikrein is secreted from the distal connecting tubule cells, which are located just distal to the major reabsorbing system. Kallikrein releases kinins, which inhibit sodium reabsorption along the collecting ducts. The kinins in the tubules are quickly destroyed by kidney-specific destroying enzymes (kininases), carboxypeptidase Y-like exopeptidase and neutral endopeptidase, which differ completely from those in plasma. Ebelactone B and poststatin were discovered as selective inhibitors of urinary kininases. Excess sodium intake causes hypertension, since sodium accumulation in the blood vessel walls increases sensitivity to hypertensive agents. Potassium, and ATP-sensitive potassium channel blockers cause renal kallikrein secretion. In bradykinin B2 receptor gene knockout mice, tissue kallikrein gene knockout mice, and kininogen-deficient rats, the knockout or deficiency does not itself induce hypertension, but these animals are salt-sensitive. Mutant kininogen-deficient (kinin-free) rats on 2% sodium intake quickly develop hypertension. Urinary kininase inhibitors reduce high blood pressure due to sodium accumulation on high sodium intake. Our ample supporting data suggest that the renal KKS prevents sodium accumulation, and that reduced levels of renal kallikrein may cause salt-sensitive hypertension. Keywords: Excess salt intake, The renal kallikrein-kinin system, Potassium, ATP-sensitive potassium channel blockers, Ebelactone B, Poststatin, Neutral endopeptidase, Renal Kallikrein-Kinin System, Renal kallikrein, Y-like exopeptidase, urinary kininases, Mutant kininogen-deficient, kallikrein-kinin system, renin-angiotensin system, systemic blood pressure, angiotensin-converting enzymes, lysyl-bradykinin, bradykinin, kallikrein-secreting cells, Henle's loop, BK-B2 antagonist, carboxypeptidase Y-like exopeptidase, human urinary kininases, epithelial Na channels, Rattus norvegicus, LMW kininogens, cerebrospinal fluid, deoxycorticosterone acetate, Weinberger's group

Intracellular Ca 2+ contributes to K +-induced increase in renal kallikrein secretion

We have reported that natriuretic effects of K + are involved in enhancement of renal kallikrein–kinin system. The study was aimed to examine 1) comparison of augmentative effects of K + on urinary KK excretion with non-specific washout effects by trichlormethiazide (thiazide), polyethyleneglycol 200 (PEG) and rapid physiological saline infusion, 2) contribution of Ca 2+ on the K +-induced increase in renal kallikrein secretion. Renal kallikrein activities were measured as fluorescence activities of methylcoumarinylamide-labeled synthetic substrate of tissue kallikrein (TK). Increases in urinary TK excretion were simultaneously observed with diuresis caused by thiazide, PEG, and rapid saline infusion. K + infusion increased urinary TK excretion with a diuretic response same as the control. K +, but not thiazide, showed an early increase in renal TK secretion dose dependently in the kidney slices. Increases in renal TK secretion persisted during treatment with K +. Neither voltage-dependent Ca 2+-channel blockers such as verapamil and nifedipine nor simultaneous treatment of EDTA affected on the K +-induced increase in renal TK secretion. While, EDTA decreased the K +-induced increases in renal TK secretion with time. Caffeine also had an early effect on the increase in renal TK secretion. K +-induced increases in renal TK secretion was demonstrated even after treatment with ryanodine or depletion of caffeine-sensitive intracellular Ca 2+ by thapsigargin. It was indicated that the increase in renal TK secretion by K + depends on the intracellular Ca 2+ and the caffeine-sensitive release of intracellular Ca 2+ may not be involved in this response. Mechanisms for the K +-induced increase in renal TK secretion needs to be further elucidated.

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

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 Renal Kallikrein-Kinin System: Its Role as a Safety Valve for Excess Sodium Intake, and Its Attenuation as a Possible Etiologic Factor in Salt-Sensitive Hypertension

The distal tubules of the kidney express the full set of the components of the kallikreinkinin system, which works independently from the plasma kallikrein-kinin system. Studies on the role of the renal kallikrein-kinin system, using congenitally kininogen-deficient Brown-Norway Katholiek rats and also bradykinin B2 receptor knockout mice, revealed that this system starts to function and to induce natriuresis and diuresis when sodium accumulates in the body as a result of excess sodium intake or aldosterone release, for example, by angiotensin II. Thus, it can be hypothesized that the system works as a safety valve for sodium accumulation. The large numbers of studies on hypertensive animal models and on essential hypertensive patients, particularly those with salt sensitivity, indicate a tendency toward the reduced excretion of urinary kallikrein, although this reduction is modified by potassium intake and impaired renal function. We hypothesize that the reduced excretion of the renal kallikrein may be attributable to a genetic defect of factor(s) in renal kallikrein secretion process and may cause salt-sensitive hypertension after salt intake.Referee: Dr. A.D. Baines, Dept. of Laboratory Medicine & Pathobiology, University of Toronto, 100 College Street, Toronto, ON, Canada, M5G 1L5

Potassium-induced increase in renal kallikrein secretion is attenuated in dissected renal connecting tubules of young spontaneously hypertensive rats

It is suggested that attenuation of the renal kallikrein–kinin system (KKS) involved the development of hypertension in young spontaneously hypertensive rats (SHR). In the present study, a comparison was made between young SHR and Wistar Kyoto rats (WKY) to examine the ability to secrete renal kallikrein from the microdissected connecting tubules (CNT) by potassium or an ATP-sensitive potassium channel blocker, 4-morpholinecarboximidine- N-1-adamantyl- N′-cyclohexylhydrochloride (PNU-37883A), both of which are renal kallikrein secretagogues. Maximum effect of potassium on kallikrein secretion was observed 10 min after placing the tubules at concentration of 20 mM. Kallikrein secretion was also increased concentration-dependently by PNU-37883A (0.1, 1, 10, and 100 μM). In the presence of EDTA, NiCl 2, verapamil, xestspongin C (an inositol 1,4,5-trisphosphate (IP 3) receptor-selective antagonist), or ruthenium red (a ryanodine-sensitive receptor blocker), potassium-induced increase in renal kallikrein secretion was inhibited. Augmentation of renal kallikrein secretion by potassium or PNU-37883A was diminished in SHR compared to WKY. These results indicate that the ability to secrete renal kallikrein by potassium was attenuated in young SHR compared with WKY. Furthermore, it is suggested that the potassium-induced renal kallikrein secretion requires an extracellular Ca 2+ entry through Ca 2+ channels including L-type Ca 2+ channels and Ca 2+ release from intracellular Ca 2+ stores through IP 3 receptor and ryanodine receptor.

Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats.

1 This study aimed to examine whether administration of potassium or ATP-sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium-induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups. 3 Administration of the KATP channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on the potassium-induced increase in renal KK secretion. 6 Renal KK secretion increased in slices of kidney cortex incubated with PNU-37883A within 10 min of superfusion. 7 In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker.

K+ loading, but not Na+ loading, and blockade of ATP-sensitive K+ channels augment renal kallikrein secretion

This study aimed to examine whether K+ loading or Na+ loading augments renal kallikrein (KK) secretion. It also investigated the effect of blockade of renal ATP-sensitive K+ channels on renal KK secretion. Rats were administered 50 mmol/kg body weight of KCl. Twelve-hour collected urine was measured for urinary excretion of K+ and Na+ and urinary activity of renal KK. Increases in urinary excretion of K+ and Na+ by K+ loading accompanied an increase in renal KK secretion. In another experiment, rats were infused intravenously with a solution of 75 mM K+ and 75 mM Na+, 150 mM Na+ or 300 mM Na+ for 150 min under anesthesia. Urinary KK activity was measured in urine collected every 30 min. Renal KK secretion began to increase within the 30 min infusion of K+ solution and persisted at more elevated levels during the infusion with K+ solution than with Na+ solutions. Furthermore, rats were given intravenous injection of ATP-sensitive K+ channel blocker, either PNU-37883A (4-morpholinecarboximidine-N-1-adamantyl-N′-cyclohexyl) at a concentration of 10 mg/kg or glibenclamide at 30 mg/kg. Renal KK secretion increased 30 min after administration of both PNU-37883A and glibenclamide. In conclusion, it may be that augmentation of renal KK secretion by K+ loading occurred through an increase in urinary K+ excretion followed by the inhibition of K+ transport from ATP-sensitive K+ channels.

P–579 - Amiloride augments renal kallikrein secretion in anesthetized rats.

P–579 - Amiloride augments renal kallikrein secretion in anesthetized rats.

O-106 - Stimulatory effect on renal kallikrein secretion by potassium

O-106 - Stimulatory effect on renal kallikrein secretion by potassium

Effect of metabolic alkalosis and metabolic acidosis on urinary kallikrein excretion of anaesthetized rats: evidence for a role of blood pH as regulator of renal kallikrein secretion

The effect of altering the acid-base status on urinary kallikrein excretion of barbiturate-anaesthetized rats was investigated. Alkalosis was induced in a group of rats by intravenous (i.v.) infusion of NaOH at 0.45 mmol x h(-1) for 30 min. Acidosis was induced in two groups of rats by i.v. infusion of HCl at 1.5 mmol x h(-1) for 30 min (uncompensated acidosis) or 0.15 mmol x h(-1) for 3 h (compensated acidosis), respectively. Time controls received 0.45 mmol x h(-1) NaCl. Rats with alkalosis excreted less kallikrein than their controls (P < 0.05). Rats with uncompensated acidosis excreted more active kallikrein (P < 0.05), whereas rats with compensated acidosis excreted similar amounts when compared with their respective controls. In rats with uncompensated acid-base derangements, the urinary kallikrein excreted per millilitre of glomerular filtrate was correlated with blood H+ activity (r = 0.99, P < 0.01). Arterial blood pressure, haematocrit, glomerular filtration rate, urine flow rate and Na+ and K+ excretions of experimental and control animals did not differ. Thus, renal kallikrein secretion into the tubular fluid appears to be regulated by blood proton activity. This, along with our previous demonstration that kallikrein inhibits HCO3- secretion into the tubular lumen (Renal Physiol 17:301-306, 1994; J Physiol (Lond) 488:163-170, 1995), indicates that this enzyme is part of a feedback loop regulating acid-base balance.

Intracellular Ca 2+ depletion and Ca 2+ channel blockers increase renal kallikrein secretion

This study examined the effect of various manipulations of intracellular Ca 2+ on kallikrein release by renal cortical slices. Increasing the extracellular Ca 2+ concentration and the addition of Ca 2+ ionophore A23187 was without effect on kallikrein release. In contrast, kallikrein release was enhanced by the addition of either extracellular or intracellular Ca 2+ chelators in Ca 2+-free medium and by two Ca 2+ channel blockers, verapamil and nifedipine. Kallikrein release was also highly enhanced in depolarising medium (10–100 mM potassium chloride). Since potassium chloride induced a dose-related increase in free cytosolic Ca 2+ which was abolished by nifedipine whereas the stimulation of kallikrein secretion persisted, a direct stimulating effect of potassium, at least at sub-physiological concentration, is suggested. Similarily, inhibition of either sodium/potassium-ATPase and Ca 2+ ATPase by ouabain and vanadium respectively, was also without effect on kallikrein secretion. Taken together, these results indicate that intracellular Ca 2+ depletion, Ca 2+ channel blockers and high extracellular K + concentrations, acting through different mechanisms, are effective stimuli for kallikrein secretion, at least in the isolated renal cortical slice.

Effect of vasopressin on renal kallikrein excretion.

In an attempt to investigate a possible interaction between vasopressin and the renal kallikrein-kinin system, renal function and urinary kallikrein excretion were monitored in trained conscious dogs and in anesthetized rats in water diuresis and in vasopressin-induced antidiuresis. Vasopressin elevated urinary kallikrein excretion in a dose-dependent way in both species, with concomitant increases in urinary osmolality and electrolyte excretion. A significant increase in kallikrein excretion was observed with a dose of vasopressin as low as 2 mU . kg-1 . h-1 in the dog and 3 mU . kg-1 . h-1 in the rat without a change in renal hemodynamics. In the rat vasopressin-induced changes in kallikrein excretion were positively correlated with changes in sodium and potassium excretion and negatively correlated with changes in free water clearance. It is concluded that vasopressin over its normal physiological range of concentration stimulates renal kallikrein secretion.