Kallikrein Excretion Research Articles

Abstract P100: Associations Between Urinary Biomarkers at Baseline and Salt and Potassium Sensitivity: The GenSalt Study

Introduction: Salt sensitivity of blood pressure is associated with an increased risk of hypertension and cardiovascular disease. Measurement methods of salt sensitivity of BP are inconvenient thus identifying biomarkers for salt sensitivity of BP has important clinical significance. Hypothesis: The urinary excretion of dopamine, kallikrein, norepinephrine and uromodulin at baseline are associated with salt sensitivity of BP. Methods: The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) (n=1887) and GenSalt Replication (n=690) studies dietary interventions included a 3-day baseline exam, 7-day low sodium feeding, a 7-day high sodium feeding, and a 7-day high sodium feeding with potassium supplementation. Baseline urinary dopamine, kallikrein, norepinephrine, and uromodulin were measured by ELISA methods. Salt and potassium sensitivity were defined as change in SBP and DBP during dietary intervention. Urinary biomarkers below limit of detection (LOD) were replaced using LOD/√2 and censored likelihood multiple imputation (CLMI). Linear models between standardized log transformed urinary biomarkers and change in SBP and DBP were assessed after adjustment for age, baseline BP, sex, education, physical activity, smoking status, alcohol intake, 24-hour sodium excretion and GenSalt cohort. Results: Norepinephrine was positively associated with SBP in CLMI models (0.10 mmHg, CI: 0.00, 0.19) and DBP in LOD/√2 models (0.31 mmHg, CI: 0.05, 0.57) and CLMI models (0.10 mmHg, CI: 0.02, 0.18) during high sodium diet. Uromodulin was associated with decreased SBP in LOD/√2 models (-0.36 mmHg, CI: -0.57, -0.14) and CLMI models (-0.19 mmHg, CI: -0.31, -0.08) during potassium supplementation. Similarly, dopamine was positively associated with DBP during high sodium diet and negatively associated with DBP during potassium supplementation. Conclusion: These data indicate urinary biomarkers dopamine, norepinephrine and uromodulin are associated with BP salt sensitivity and may be used in risk stratification.

Relation of family history of hypertension to platelet aggregation, ratio of total cholesterol to HDL cholesterol and urinary kallikrein excretion.

Some of the relatively easily measurable and possibly hypertension-associated parameters were evaluated in thirty normotensive young subjects divided into the PHT (either parent hypertensive) group and the PNT (both parents normotensive) group. In subjects of the PHT group, the platelet aggregating sensitivity to the arachidonic acid and the ratio of total cholesterol to HDL cholesterol were significantly (p less than 0.05) increased while urinary kallikrein excretion was decreased without simultaneously significant elevation of blood pressure. The enhanced platelet aggregating sensitivity to the arachidonic acid and the increased ratio of total cholesterol to HDL cholesterol suggest that subjects with a positive family history of hypertension might have a greater tendency to atherosclerosis and could contribute to the development of essential hypertension. Decreased urinary kallikrein excretion suggests that the vasodepressive activity of the kallikrein-kinin system might be inhibited in subjects with a positive family history of hypertension.

Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity.

Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria

The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

Antihypertensive Role of Tissue Kallikrein in Hyperaldosteronism in the Mouse

Tissue kallikrein (TK) is synthesized in arteries and distal renal tubule, the main target of aldosterone. Urinary kallikrein excretion increases in hyperaldosteronism. We tested the hypothesis that TK is involved in the cardiovascular and renal effects of high aldosterone. Kallikrein-deficient mice (TK-/-), and wild-type (WT) littermates, studied on two different genetic backgrounds, were treated with aldosterone and high-NaCl diet for 1 month. Control mice received vehicle and standard NaCl diet. Treatment induced 5- to 7-fold increase in plasma aldosterone, suppressed renin secretion, and increased urinary TK activity. In 129SvJ-C57BL/6J mice, blood pressure monitored by radiotelemetry was not different between control TK-/- and WT mice. In TK-/- mice, aldosterone induced larger increases in blood pressure than in WT mice (+47 vs. +27 mm Hg; genotype-treatment interaction, P < 0.05). Night-day difference was also exacerbated in treated TK-/- mice (P < 0.01). Moderate cardiac septal hypertrophy was observed in hypertensive animals without major change in heart function. Aldosterone-salt increased kidney weight similarly in both genotypes but induced a 2-fold increase in renal mRNA abundance of epithelial sodium channel subunits only in TK-/- mice. The hypertensive effect of TK deficiency was also documented in treated C57BL/6J mice. In this strain, aldosterone-induced hypertension was only observed in TK-/- mice (+16 mm Hg, P < 0.01). These findings show that TK deficiency exacerbates aldosterone-salt-induced hypertension. This effect may be due at least in part to enhanced sodium reabsorption in the distal nephron aggravating sodium retention. The study suggests that kallikrein plays an antihypertensive role in hyperaldosteronism.

Tissue kallikrein activation of the epithelial Na channel

Epithelial Na Channels (ENaC) are responsible for the apical entry of Na(+) in a number of different epithelia including the renal connecting tubule and cortical collecting duct. Proteolytic cleavage of γ-ENaC by serine proteases, including trypsin, furin, elastase, and prostasin, has been shown to increase channel activity. Here, we investigate the ability of another serine protease, tissue kallikrein, to regulate ENaC. We show that excretion of tissue kallikrein, which is secreted into the lumen of the connecting tubule, is stimulated following 5 days of a high-K(+) or low-Na(+) diet in rats. Urinary proteins reconstituted in a low-Na buffer activated amiloride-sensitive currents (I(Na)) in ENaC-expressing oocytes, suggesting an endogenous urinary protease can activate ENaC. We next tested whether tissue kallikrein can directly cleave and activate ENaC. When rat ENaC-expressing oocytes were exposed to purified tissue kallikrein from rat urine (RTK), ENaC currents increased threefold in both the presence and absence of a soybean trypsin inhibitor (SBTI). RTK and trypsin both decreased the apparent molecular mass of cleaved cell-surface γ-ENaC, while immunodepleted RTK produced no shift in apparent molecular mass, demonstrating the specificity of the tissue kallikrein. A decreased effect of RTK on Xenopus ENaC, which has variations in the putative prostasin cleavage sites in γ-ENaC, suggests these sites are important in RTK activation of ENaC. Mutating the prostasin site in mouse γ-ENaC (γRKRK186QQQQ) abolished ENaC activation and cleavage by RTK while wild-type mouse ENaC was activated and cleaved similar to that of the rat. We conclude that tissue kallikrein can be a physiologically relevant regulator of ENaC activity.

Renal kallikrein excretion and epigenetics in human acute kidney injury: Expression, mechanisms and consequences

BackgroundRenal kallikrein (KLK1) synthesis and urinary excretion are reportedly diminished during AKI (acute kidney injury) in animal models, and provision of kallikrein abrogates renal injury in this setting, but data in human AKI is limited. Therefore we first examined KLK1 renal excretion in human AKI, and then probed potential endocrine and epigenetic mechanisms for its alterations.MethodsKLK1 enzymatic activity excretion was evaluated in urine from patients with established or incipient AKI, versus healthy/non-hospital as well as ICU controls. Endocrine control of KLK1 excretion was then probed by catecholamine and aldosterone measurements in established AKI versus healthy controls. To examine epigenetic control of KLK1 synthesis, we tested blood and urine DNA for changes in promoter CpG methylation of the KLK1 gene, as well as LINE-1 elements, by bisulfite sequencing.ResultsPatients with early/incipient AKI displayed a modest reduction of KLK1 excretion, but unexpectedly, established AKI displayed substantially elevated urine KLK1 excretion, ~11-fold higher than healthy controls, and ~3-fold greater than ICU controls. We then probed potential mechanisms of the change. Established AKI patients had lower SBP, higher heart rate, and higher epinephrine excretion than healthy controls, though aldosterone excretion was not different. Promoter KLK1 CpG methylation was higher in blood than urine DNA, while KLK1 methylation in blood DNA was significantly higher in established AKI than healthy controls, though KLK1 methylation in urine tended to be higher in AKI, directionally consistent with earlier/incipient but not later/established changes in KLK1 excretion in AKI. On multivariate ANOVA, AKI displayed coordinate changes in KLK1 excretion and promoter methylation, though directionally opposite to expectation. Control (LINE-1 repetitive element) methylation in blood and urine DNA was similar between AKI and controls.ConclusionsUnexpectedly, increased KLK1 excretion in AKI patients was found; this increase is likely to be due in part to increments in adrenergic tone during BP depression. Epigenetic changes at KLK1 may also play a role in early changes of KLK1 expression and thus AKI susceptibility or recovery.

Renal Responses to Magnesium Lithospermate B

Renal responses to magnesium lithospermate B isolated from Salviae miltiorrhizae radix were examined in normal rats. Urinary sodium, potassium, prostaglandin E2 and kallikrein excretion was significantly increased after magnesium lithospermate B administration, whereas excretion of urinary 6-keto-prostaglandin F1 alpha and thromboxane B2 was unchanged. Rats administered with the drug also revealed a slight elevation of plasma renin activity and the levels of angiotensins I and II. Plasma aldosterone was decreased slightly. No significant changes were observed in angiotensin-converting enzyme or blood pressure.

本態性高血圧症における尿中カリクレイン,レニン・アンジオテンシン系および尿中電解質排泄について--多施設外来通院患者での検討

本態性高血圧症における尿中カリクレイン,レニン・アンジオテンシン系および尿中電解質排泄について--多施設外来通院患者での検討

Essential hypertension in adolescents and children: Recent advances in causative mechanisms

Essential hypertension is the most common form of hypertension in adults, and it is recognized more often in adolescents than in younger children. It is well known that the probability of a diagnosis of essential hypertension increases with age from birth onward. The initiation of high blood pressure burden starts in childhood and continues through adolescence to persist in the remaining phases of life. The genesis of essential hypertension is likely to be multifactorial. Obesity, insulin resistance, activation of sympathetic nervous system, sodium homeostasis, renin-angiotensin system, vascular smooth muscle structure and reactivity, serum uric acid levels, genetic factors and fetal programming have been implicated in this disorder. In addition, erythrocyte sodium transport, the free calcium concentration in platelets and leukocytes, urine kallikrein excretion, and sympathetic nervous system receptors have also been investigated as other possible mechanisms. Obesity in children appears to be the lead contributor of essential hypertension prevalence in children and adolescents. Suggested mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of renin-angiotensin-aldosterone, and altered vascular function. The etiopathogenesis of essential hypertension in children and adolescents appears to closely resemble that of adults. The minor variations seen could probably be due to the evolving nature of this condition. Many of the established mechanisms that are confirmed in adult population need to be replicated in the pediatric age group by means of definitive research for a better understanding of this condition in future.

Effect of magnesium lithospermate B on the renal and urinary kallikrein activities in rats with adenine-induced renal failure.

A study was conducted to examine the effect of magnesium lithospermate B on both the urinary and renal total and active kallikrein and prokallikrein in rats with adenine-induced renal failure. In rats given magnesium lithospermate B at a dose of 10 mg/kg body weight/day for 12 days, significant increases of urinary total and active kallikrein were associated with significant increases of urine volume and urinary total and active kallikrein were associated with significant increases of urine volume and urinary creatinine excretion. The renal total and active kallikrein levels were also significantly elevated by the treatment with magnesium lithospermate B. On day 24, the urinary excretion of total and active kallikrein and prokallikrein was significantly increased. Concomitantly, a significant increase in renal kallikrein (total, active and pro-) was found in the rats given magnesium lithospermate B. A significant relationship existed between the urinary creatinine and active kallikrein excretion. These results suggest that magnesium lithospermate B may stimulate the synthesis of kallikrein and/or conversion to active kallikrein, thus improving renal function.

Hormonal factors influencing fractional excretion of filtered sodium in normal children.

Fractional excretion of filtered sodium (FENa), plasma renin activity (PRA), urinary kallikrein excretion and main urinary metabolite of prostaglandin F2 alpha (PGF MUM) excretion were measured to evaluate the relationship between FENa and these hormonal factors in 33 healthy children aged 8 to 15 years. FENa showed a significant negative correlation with PRA and PGF MUM excretion (P less than 0.001, P less than 0.01, respectively), suggesting that PRA and PGF MUM are useful investigations in evaluating FENa. Especially PRA is often measured routinely and should be measured first, which may provide useful pathophysiological information on the genesis of abnormal FENa.

Urinary kallikrein excretion is related to renal function change and inflammatory status in chronic kidney disease patients receiving angiotensin II receptor blocker treatment

This study was to evaluate the correlation of urinary kallikrein to renal function, proteinuria and urinary cytokines in chronic kidney disease patients in a longitudinal follow up. We measured urinary kallikrein and cytokines in 50 patients who were followed up for 12 months. Using regression model we found that the kallikrein excretion (estimated by log kallikrein/creatinine) was positively correlated to log estimated glomerular filtration rate in the beginning and the end of follow up (P = 0.049 and 0.006, respectively). No correlation existed between kallikrein excretion and proteinuria. The kallikrein excretion decreased after 12 months of follow up, which was also associated with the decrease of log estimated glomerular filtration rate. There was a significant positive correlation between the log urinary kallikrein and monocyte chemoattractant protein-1 (MCP-1) concentration (correlation coefficient = 0.277; P = 0.049). Urinary kallikrein excretion was also positively correlated with serum MCP-1 level (correlation coefficient = 0.431; P = 0.002). No correlation existed between urinary kallikrein and transforming growth factor beta-1 or tumour necrosis factor-alpha concentration. Urinary kallikrein excretion is positively correlated to renal function, serum and urinary inflammatory mediator MCP-1 in chronic kidney disease patients. These findings indicate that urinary kallikrein excretion may reflect the change of renal function and kidney inflammatory status.

Defective ENaC Processing and Function in Tissue Kallikrein-deficient Mice

An inverse relationship exists between urinary tissue kallikrein (TK) excretion and blood pressure in humans and rodents. In the kidney TK is synthesized in large amounts in the connecting tubule and is mainly released into the urinary fluid where its function remains unknown. In the present study mice with no functional gene coding for TK (TK-/-) were used to test whether the enzyme regulates apically expressed sodium transporters. Semiquantitative immunoblotting of the renal cortex revealed an absence of the 70-kDa form of gamma-ENaC in TK-/- mice. Urinary Na+ excretion after amiloride injection was blunted in TK-/- mice, consistent with reduced renal ENaC activity. Amiloride-sensitive transepithelial potential difference in the colon, where TK is also expressed, was decreased in TK-/- mice, whereas amiloride-sensitive alveolar fluid clearance in the lung, where TK is not expressed, was unchanged. In mice lacking the B2 receptor for kinins, the abundance of the 70-kDa form of gamma-ENaC was increased, indicating that its absence in TK-/- mice is not kinin-mediated. Incubation of membrane proteins from renal cortex of TK-/- mice with TK resulted in the appearance of the 70-kDa band of the gamma-ENaC, indicating that TK was able to promote gamma-ENaC cleavage in vitro. Finally, in mouse cortical collecting ducts isolated and microperfused in vitro, the addition of TK in the luminal fluid increased significantly intracellular Na+ concentration, consistent with an activation of the luminal entry of the cation. The results demonstrate that TK, like several other proteases, can activate ENaC in the kidney and the colon.

Effect of Prepuberal Gonadectomy upon Aldosterone Levels in Female and Male SHR: Interaction between Blood Pressure and Kallikrein Kinin System

It has been suggested that an abnormal activity of the hypothalamic-pituitary-adrenal-gonadal axis may be implicated in the pathogenesis of spontaneously hypertensive rats (SHR) blood pressure hypertension. However, it is widely known that the kallikrein-kinin system plays a role in blood pressure regulation in this strain, because an inverse relation between blood pressure and urinary kallikrein excretion has been reported. It was of our interest to study how early suppression of sexual hormones affected blood pressure regulation in SHR and urinary kallikrein excretion and to elucidate the involved mechanisms. For these purpose, SH and Wistar-Kyoto (WKY) rats blood pressure, renal function, and hormonal profile were studied after prepuberal gonadectomy starting at 4 weeks of age throughout until the 12th week of age. Results were compared with those of untreated SH and WKY rats of either sex. The response to blocking agents against aldosterone and kallikrein-kinin system also were evaluated. Systolic blood pressure increased progressively in male and female SHR 12 weeks of age. Systolic blood pressure was higher in male than in female SHR, but urinary kallikrein was lower in male SHR. Prepuberal gonadectomy induced a significant decrease in systolic blood pressure in male and in female SHR at 12 weeks of age, accompanied by an increase in urinary kallikrein in male and in female SHR. Plasma aldosterone increased markedly in female and male SHR after gonadectomy. No concurrent changes in plasma renin activity or corticosterone levels were observed. The aldosterone receptor antagonist and the kallikrein inhibitor treatment blunted the blood pressure lowering effect of gonadectomy and diminished urinary kallikrein excretion. Results support the existence of a sexual dimorphism related to hypertension and urinary kallikrein and suggest an interaction among the kallikrein-kinin system, sexual hormones, and mineralocorticoids in the neonatal programming of hypertension.

Significance of the tissue kallikrein promoter and transforming growth factor-β1 polymorphisms with renal progression in children with vesicoureteral reflux

Tissue kallikrein regulates blood circulation. Low urinary kallikrein excretion was associated with hypertension and renal disease in blacks. The polymorphic KLK1 promoter includes -130 GN coupled with multiple single base substitutions. The -130 G12 allele in the KLK1 promoter was associated with lower transcriptional activity and hypertensive end-stage renal disease (ESRD) in blacks. Transforming growth factor-beta1 (TGF-beta1) regulates matrix production, and induces fibrosis in a variety of tissues. High circulating TGF-beta1 levels mediating renal fibrosis and loss of function in transgenic mice. The -509 T allele in the TGF-beta1 promoter showed marginally higher transcriptional activity, and was associated with increased TGF-beta1 production in humans. The aim of this study was to investigate whether the tissue KLK1 promoter and TGF-beta1 polymorphism are involved in primary vesicoureteric reflux (VUR) with renal progression in children. Seventy-four primary VUR children were studied with regular annual follow-up for more than 18 years, all of them more than grade II (diagnosed by voiding cystourethroradiography). All of them were born before 1984. Patients were classified into two groups according to the renal function with progressive deterioration or not. Patients with baseline creatinine clearance (CCr) less than 25 mL/min were defined as having chronic renal insufficiency (CRI). The TGF-beta1 -509 T-C polymorphism was analyzed by Bsu36I restriction fragment length polymorphism (RFLP)-polymerase chain reaction (PCR). In KLK1 promoter, the -130 GN length polymorphism and multiple single base substitutions were analyzed by electrophoresis of fluoresced PCR products in sequencing gels, single strand conformation polymorphism (SSCP), allele-specific PCR, and DNA sequencing. Patients' TGF-beta1 and KLK1 promoter polymorphisms were evaluated for association with VUR susceptibility and progression in Taiwanese children. Annual echocardiography study was used to evaluate left ventricular mass index (LVMI). Four alleles were identified in the complex KLK1 promoter: A (-130 G10), B (-130 G2CG7), H (-130 G11), and K (-130 G12). The polymorphic KLK1 promoter showed no association with VUR susceptibility. However, the frequency distribution of KLK1 promoter among VUR patients with or without CRI (A, 50.0% and 67.5%; B, 17.9% and 8.3%; H, 14.3% and 18.3%; K, 17.9% and 5.8%, respectively) was statistically different (P = 0.008). Significantly higher K allele frequency was present in primary VUR with CRI children, as it was in the renal survival curve study. A significant increase of LVMI was also found in the A allele group compared with the non-A allele group of KLK1 promoter gene at the age of 18 years old with renal progression. The TGF-beta1 gene polymorphism was determined, and we found significant over-representation of the TT genotype in primary VUR patients with CRI compared with normal renal function (P= 0.0035). The K allele of KLK1 promoter and TT genotype of TGF-beta1 may be a genetic KLK1 -130 GN and -128 G-C, and the susceptibility factor contributing to progressive renal deterioration in Taiwanese primary VUR children.

Loss of sodium modulation of plasma kinins in human hypertension.

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 renin-angiotensin-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 < 0.001 overall) and the plasma angiotensin-converting enzyme (P = 0.017) and increased plasma renin activity (P < 0.001) and serum aldosterone (P < 0.001). There was an interactive effect of salt intake and hypertension on plasma BK 1-5 (P = 0.043), with BK 1-5 significantly lower during low compared with high salt intake in normotensive (24.7 +/- 2.6 versus 34.9 +/- 5.6 fmol/ml, P = 0.002) but not hypertensive subjects (30.6 +/- 4.6 versus 27.5 +/- 2.8 fmol/ml, P = 0.335). In normotensives, the change in plasma BK 1-5 from high to low salt intake correlated with the change in MAP (r = 0.533, P = 0.004). Urinary kallikrein was higher during low compared with high salt intake (P < 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.

Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension

Background Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K +, a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K +) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans. Methods Nineteen healthy normotensive young men ( n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA. Results African Americans had diminished urinary excretion of not only kallikrein ( P = .007), but also K + ( P < .001) and aldosterone ( P = .015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K +; P = .019) or directly (by the exogenous mineralocorticoid fludrocortisone; P = .027), despite achievement of substantial increments in K + excretion after KCl ( P = .002), and multiple other mineralocorticoid effects after fludrocortisone ( P = .005). The kallikrein increment after KCl was best predicted by renin activity ( P = .001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group ( P > .4). Conclusions Restoration of K + and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.

Different response of intracerebroventricular cadmium administration on blood pressure in normal and low urinary kallikrein rats

Cadmium intracerebroventricular (i.c.v.) administration, at definite concentrations, induces a dose-dependent increase in the systemic blood pressure. Kallikreins are suggested to be important regulators of cardiovascular function. We evaluated the effects of 10 μg i.c.v. cadmium on mean blood pressure (MBP) and several urinary parameters such as 24 h urine volume, sodium and potassium excretion and osmolality in a rat strain inbred for low urinary kallikrein and in normal-kallikrein Wistar rats. Low-kallikrein rats (LKR) showed an increase in MBP that, after an initial peak (27% from baseline), persisted higher than basal levels (10%) over 24 h. In normal-kallikrein rats (NKR) a different reaction of blood pressure to cadmium was observed, causing a temporary increase (26% from baseline) of the systemic blood pressure, that returned to normal values within 2 h. In addition, LKR showed a considerable reduction in the urinary volume (UV; 43.0±20 ml/24 h versus 13.2±6 ml/24 h, P<0.006), with an increase in the urinary osmolality ( U Osm; 500±210 mOsm/l versus 1391±245 mOsm/l, P<0.0002). Sodium ( U Na; 1761±432 μEq/24 h versus 1156±522 μEq/24 h, P<0.03) and potassium excretion ( U K; 2186±482 μEq/24 h versus 936±299 μEq/24 h, P<0.0006) were both significantly reduced. No changes in UV, U Osm and U K were observed in normal urinary kallikrein rats with the exception of U Na excretion that was significantly increased (667±274 μEq/24 h versus 1725±300 μEq/24 h, P<0.03). These results suggest that a genetically determined defect in urinary kallikrein excretion leads to a different hypertensive response to i.c.v. cadmium and to a different renal excretion of electrolytes. Perhaps the differences of blood pressure response could be due, at least in part, to a different sensitivity of LKR to cadmium: this implies a complex and articulate hypertensive effect of cadmium involving more systems than those supposed so far.

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