Do cysteine residues regulate transient receptor potential canonical type 6 channel protein expression?

The regulation of calcium influx through transient receptor potential canonical type 6 (TRPC6) channel is mandatory for the activity of human monocytes. We submit the first evidence that cysteine residues of homocysteine (HC) or acetylcysteine (ACC) affect TRPC6 expression in human monocytes. We observed that patients with chronic renal failure had significantly elevated HC levels and TRPC6 mRNA expression levels in monocytes compared with control subjects. We further observed that administration of HC or ACC significantly increased TRPC6 channel protein expression compared with control conditions. We, therefore, hypothesize that cysteine residues increase TRPC6 channel protein expression in humans.

N-acetylcysteine improves arterial vascular reactivity in patients with chronic kidney disease.

BACKGROUND: Patients with stage 5 chronic kidney disease show increased cardiovascular morbidity and mortality that are partly related to impaired arterial vascular reactivity. We investigated whether intravenous administration of the antioxidant acetylcysteine improves arterial vascular reactivity in these patients. METHODS: Arterial vascular reactivity was determined during reactive hyperemia by photoplethysmography of digital pulse waves in a randomized, prospective, placebo-controlled cross-over study of 24 patients with stage 5 chronic kidney disease with and without infusion of acetylcysteine during hemodialysis. Acetylcysteine (5 g in 5% glucose in a final volume of 50 ml) was continuously administered intravenously during one hemodialysis session. RESULTS: In the absence of acetylcysteine, the reflective index was 38.5 +/- 9.4 (mean +/- SD; n = 24) at baseline and 33.8 +/- 9.9 during reactive hyperemia, immediately after the hemodialysis session; thus there was no significant vasodilatation (p > 0.05), indicating impaired arterial vascular reactivity in these patients. However, when the hemodialysis session in the same patients was performed in the presence of acetylcysteine, the reflective index significantly decreased from 37.9 +/- 8.6 at baseline to 30.2 +/- 10.3 during reactive hyperemia (n = 24; p < 0.01). CONCLUSION: The present study shows that intravenous administration of acetylcysteine during hemodialysis significantly improves arterial vascular reactivity during reactive hyperemia.

Mortality risk in hemodialysis patients with increased arterial stiffness is reduced by attainment of classical clinical performance measures.

BACKGROUND: We determined whether attainment of classical clinical performance measures for hemodialysis care improves survival in hemodialysis patients with increased arterial stiffness. METHODS: We performed a prospective cohort study of 538 hemodialysis patients with a median follow-up of 19 months (interquartile range 8-30). Arterial stiffness was measured using applanation tonometry. Clinical performance measure targets were hemoglobin value >or=110 g/l, serum albumin value >or=37 g/l and measured single-pool Kt/V urea value >or=1.2. RESULTS: During follow-up, 217 patients (40%) died. In non-survivors, arterial stiffness of large arteries (S1) was significantly higher compared with survivors (p = 0.0002). An analysis of hemodialysis patients who were alive 18 months after inclusion into the study showed that survival was significantly longer in those patients that met >or=2 clinical performance measure targets compared with patients that met

Impaired vascular reactivity in patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) show increased cardiovascular morbidity. We hypothesized that vascular properties which can be routinely evaluated noninvasively are related to different stages of CKD and their clinical and biochemical characteristics. METHODS: Arterial vascular properties were quantified by the reflective index using digital photoplethysmography in 260 patients with CKD. Patients were grouped according to estimated glomerular filtration rate (eGFR). Additional measurements were performed in 50 healthy control subjects. RESULTS: In patients with CKD stage 1 and 2 (n = 115; age 65 +/- 1 years) the reflective index was 30 +/- 1%, whereas in patients with CKD stage 3 and 4 (n = 60; age 72 +/- 1 years) the reflective index was 36 +/- 1%, and in patients with CKD stage 5 (n = 85; age 64 +/- 1 years) the reflective index was 36 +/- 1% (p < 0.01 by Kruskal-Wallis test) indicating increased arterial stiffness in advanced CKD. Arterial vascular reactivity was significantly impaired in patients with advanced stages of CKD (stage 1 and 2, 78 +/- 12%; stage 3 and 4, 32 +/- 12%; stage 5, 33 +/- 12%; p < 0.01). Univariate analysis showed a significant correlation of the reflective index and eGFR (Pearson r = -0.24; p < 0.0001). Multivariate regression analysis showed an independent association of the reflective index and eGFR (adjusted correlation coefficient, -0.24; p < 0.001). CONCLUSION: The advanced stages of CKD are associated with increased vascular stiffness and impaired vascular reactivity and these changes are already present in CKD stage 3 and 4.

Phenylacetic acid and arterial vascular properties in patients with chronic kidney disease stage 5 on hemodialysis therapy.

BACKGROUND: Phenylacetic acid (PAA) is a recently described uremic toxin that inhibits inducible nitric oxide synthase expression and plasma membrane calcium ATPase and may therefore also be involved in remodeling of arteries. Such vascular effects have not been evaluated yet in patients with chronic kidney disease stage 5. METHOD: We prospectively measured the plasma concentrations of PAA using nuclear magnetic resonance spectroscopy in 50 patients with chronic kidney disease stage 5 (37 men, 13 women) on maintenance hemodialysis. Arterial vascular properties were quantified by the reflective index obtained from digital photoplethysmography. RESULTS: During the hemodialysis session the plasma PAA concentration was reduced from 3.38 +/- 0.24 mmol/l (mean +/- SEM; median, 2.85 mmol/l; interquartile range, 2.02-4.52 mmol/l) to 2.25 +/- 0.11 mmol/l (median, 2.06 mmol/l; interquartile range, 1.62-2.86 mmol/l; n = 50; p < 0.001). There was a significant correlation between the PAA concentration and the reflective index before the start of the hemodialysis session. CONCLUSION: The study demonstrates an association of PAA and arterial vascular properties in patients with chronic kidney disease stage 5.

Increased store-operated and 1-oleoyl-2-acetyl-sn-glycerol-induced calcium influx in monocytes is mediated by transient receptor potential canonical channels in human essential hypertension.

OBJECTIVE: Activation of nonselective cation channels of the transient receptor potential canonical (TRPC) family has been associated with hypertension. Whether store-operated channels, which are activated after depletion of intracellular stores, or second-messenger-operated channels, which are activated by 1-oleoyl-2-acetyl-sn-glycerol, are affected in essential hypertension is presently unknown. METHODS: Using a polymerase chain reaction, an in-cell western assay and the fluorescent dye technique we studied TRPC3, TRPC5, and TRPC6 expression and store-operated and 1-oleoyl-2-acetyl-sn-glycerol-induced calcium influx into human monocytes in 19 patients with essential hypertension and in 17 age-matched and sex-matched normotensive control individuals. RESULTS: We observed a significantly increased expression of TRPC3 and TRPC5, but not TRPC6, in essential hypertension. Store-operated calcium influx was significantly elevated in essential hypertension. Store-operated calcium influx was reduced by the inhibitor 2-aminoethoxydiphenylborane, specific TRPC3 and TRPC5 knockdown, but not TRPC6 knockdown using gene silencing by RNA interference. 1-Oleoyl-2-acetyl-sn-glycerol-induced calcium influx and barium influx were also significantly elevated in essential hypertension. The 1-oleoyl-2-acetyl-sn-glycerol-induced cation influx was reduced by TRPC3 and TRPC5 knockdown. CONCLUSION: We demonstrated an increased TRPC3 and TRPC5 expression and a subsequently increased store-operated calcium influx and increased 1-oleoyl-2-acetyl-sn-glycerol-induced cation influx in monocytes of patients with essential hypertension. This increased activation of monocytes through TRPC channels in patients with essential hypertension may promote vascular disease in these patients.