Effect of chronic kidney disease on macrophage cholesterol efflux.

AIMS: Patients with chronic kidney disease (CKD) have a high risk to develop atherosclerosis. The capacity of high-density lipoproteins (HDL) or serum to accept cholesterol from macrophages and the capacity of macrophages to export excess cholesterol are critical for the atheroprotective role of reverse cholesterol transport. HDL cholesterol acceptor capacity was reported to be decreased in middle aged hemodialysis patients, but the role of confounding factors remains unclear. MAIN METHODS: We measured the cholesterol acceptor capacity (CAC) of HDL or serum in 12 pediatric and 17 young adult patients with CKD stages 3-5, 14 young adult hemodialysis patients and 15 adult renal transplant recipients without associated diseases and matched controls using THP-1 macrophages. Moreover we studied the cholesterol export capacity (CEC) of patients' monocyte-derived macrophages (HMDMs) to control serum or HDL. KEY FINDINGS: In adults with CKD stages 3-5 serum CAC was slightly increased, whereas CEC of HMDMs was unaltered in both, adult and pediatric patients. In hemodialysis patients, however, serum CAC was markedly reduced to 85±11% of control (p<0.001), presumably due to low serum apolipoprotein A-I. Interestingly, CEC of HMDMs from dialysis patients was increased. In transplant patients no alterations were found. SIGNIFICANCE: CKD without hemodialysis does not reduce cholesterol export from macrophages. Hemodialysis patients might benefit from therapies aiming to restore serum CAC by increasing apolipoprotein A-I. The enhanced export of cholesterol by HMDMs from dialysis patients may represent an adaptive response.

Carbamoylated free amino acids in uremia: HOCl generates volatile protein modifying and cytotoxic oxidant species from N-carbamoyl-threonine but not threonine.

N-carbamoylation is the non-enzymatic reaction of cyanate with amino groups. Due to urea-formed cyanate in uremic patients beside carbamoylated proteins also free amino acid carbamoylation has been detected, a modification which has been linked to disturbed protein synthesis as NH(2)-derivatisation interferes with peptide bond formation. HOCl the product of the activated MPO/H(2)O(2)/Cl(-) system is known to react with the NH(2)-group of free amino acids to form chloramines which could exert some protective effect against protein modification and cytotoxicity induced by HOCl. As N-carbamoylation may inhibit formation of chloramines we have used N-carbamoyl-threonine as a model amino acid to study its ability to limit the reactivity of HOCl with proteins (LDL and human serum albumin) and cells (THP-1 monocytes and coronary artery endothelial cells). The data indicate that N-carbamoylation completely abolished the protein- and cell-protective effect of threonine against HOCl attack. In contrast to threonine the reaction of HOCl with carbamoyl-threonine resulted in the formation of volatile oxidant species with protein modifying and cytotoxic potential. The volatile lipophilic inorganic monochloramine (NH(2)Cl) was identified as a breakdown product of this reaction.

The effect of estrogen on dopamine and serotonin receptor and transporter levels in the brain: an autoradiography study.

The aim of the present study was to elucidate the effect of estrogen on dopaminergic and serotonergic regulation of prepulse inhibition (PPI) by measuring its effects on the density of dopamine transporters (DAT), dopamine D(1) and D(2) receptors, serotonin transporters (SERT), serotonin-1A (5-HT(1A)) and 5-HT(2A) receptors using radioligand binding autoradiography. Three groups of female Sprague-Dawley rats were compared: sham-operated controls, untreated ovariectomized (OVX) rats and OVX rats with a 17beta-estradiol implant (OVX+E). These groups were identical to our previous prepulse inhibition (PPI) studies, allowing comparison of the results. Results showed that in the nucleus accumbens, DAT levels were 44% lower in OVX rats than in intact controls. Estrogen treatment completely reversed the effect of OVX in this brain region to levels similar to those in intact controls. Dopamine D(2) receptor density was increased in OVX rats by 28% in the nucleus accumbens and 25% in the caudate nucleus compared to intact controls. Estrogen treatment reversed this increase and, in addition, reduced dopamine D(2) receptor levels by a further 25% and 20%, respectively, compared to intact control rats. There were no differences between the groups with respect to the densities of dopamine D(1) receptors, SERT, 5-HT(1A) receptors or 5-HT(2A) receptors. These results show effects of estrogen treatment on central indices of dopaminergic, but not serotonergic function. The observed changes do not provide a direct overlap with the effects of these estrogen treatment protocols on drug-induced disruptions of PPI, but it is possible that a combination of effects, i.e. on both DAT and dopamine D(2) receptor density, is involved. These data could also be relevant for our understanding of the potential protective effect of estrogen treatment in schizophrenia.