Erythropoiesis is maintained by the hormone erythropoietin (Epo) binding to its cognate receptor (EpoR) on erythroid progenitor cells. The Epo-EpoR interaction initiates a signal transduction process that regulates the survival, growth and differentiation of these cells. Originally perceived as highly lineage-restricted, Epo is now recognised to have pleiotropic effects extending beyond the maintenance of red cell mass. Functional interactions between Epo and EpoR have been demonstrated in numerous cells and tissues. EpoR expression on neoplastic cells leads to concern that recombinant human erythropoietin, used to treat anaemia in cancer patients, may augment tumour growth. Here we demonstrate that EPO, at pharmacological concentrations, can activate three major signalling cascades, viz. the Jak2/STAT5, Ras/ERK and PI3K/Akt pathways in non-small cell lung carcinoma (NSCLC) cell lines. EpoR synthesis is normally under the control of GATA-1, but NSCLC cells exhibit decreased GATA-1 levels compared to GATA-2, -3 and -6, suggesting that GATA-1 is not essential for EpoR production. The increased Epo-induced signalling was not associated with a growth advantage for the NSCLC cells.

Human serum paraoxonase (aryldialkylphosphatase, EC 3.1.8.1; PON1) and human serum platelet-activating factor acetylhydrolase (1-alkyl-2-acetyl-glycero-phosphocholine esterase, 1-alkyl-2-acetyl- sn -glycero-3-phosphocholine acetohydrolase, EC 3.1.1.47; PAF-AH) are associated with HDL (1)(2). PAF-AH is also found in LDL and lipoprotein(a) \[Lp(a)\] (3). Recently, paraoxonase and PAF-AH have been shown to inhibit the oxidative modification of LDL (4)(5). Furthermore, paraoxonase and PAF-AH can destroy active lipids in mildly oxidized LDL and hence may protect against the induction of inflammatory responses in arterial wall cells (6)(7). Oxidation of LDL is recognized as a key early stage in the development of atherosclerosis, leading to uptake of LDL by the macrophage scavenger receptor and hence to formation of foam cells (8). Thus, there is the potential for HDL-associated paraoxonase and PAF-AH to directly inhibit these processes. The PON1 gene has two common polymorphisms at amino acids 55 and 192 (9). The 192 polymorphism leads to a Glu→Arg substitution and results in two different isoforms that have high and low activity towards paraoxon as substrate (9)(10). It has been suggested that paraoxonase and PAF-AH work in concert to detoxify lipid peroxides in LDL and may therefore have antiatherogenic properties (6). Patients with chronic renal failure are at a greatly increased risk of developing cardiovascular disease. This is only partly explained by an increased prevalence of conventional risk factors (11)(12). Increased susceptibility of LDL to oxidation has been reported in chronic renal failure (13)(14), although other studies have failed to confirm this finding (15)(16). In view of the ability of HDL to protect LDL against oxidation, the aim of our study was therefore to investigate the activities of serum paraoxonase/arylesterase and PAF-AH in patients with chronic renal failure and hence to assess whether changes …

Recent studies have suggested that an inherited predisposition to essential hypertension may increase susceptibility to nephropathy for patients with IDDM. Essential hypertension has been linked to the angiotensinogen (AGT) gene in genetic linkage studies in American and European populations. A molecular variant (M235T), which has a functional effect, has been described with highest plasma AGT levels being associated with the TT genotype. In a case-control study, we have evaluated the role of this functional genetic marker in patients with IDDM and nephropathy and in IDDM patients without nephropathy. We studied 195 IDDM patients, of whom 95 had established diabetic nephropathy; the remaining 100 patients, who had no evidence of microalbuminuria, served as control subjects. All patients were whites born in Northern Ireland. The point mutation in the AGT gene was analyzed using restriction typing. The background frequency of the M235T variant was assessed in 80 healthy blood donors, and the TT genotype was present in 9%. This genotype occurred in 8% of control IDDM patients without nephropathy and 19% of IDDM patients with nephropathy (P = 0.025). The odds ratio for diabetic nephropathy associated with the TT genotype was 2.7 (95% CI 1.04–7.52). There was no relationship between blood pressure and AGT genotypes in the control group. We cannot exclude the possibility that the observed association in the nephropathy group is due to an association between AGT genotype and hypertension. This evidence may help to explain the predisposition to diabetic nephropathy afforded by hypertension and merits further investigation.