We have recently cloned the mouse activity-dependent neuroprotective protein (ADNP). Here, we disclose the cloning of human ADNP (hADNP) from a fetal brain cDNA library. Comparative sequence analysis of these two ADNP orthologs indicated 90% identity at the mRNA level. Several single nucleotide polymorphic sites were noticed. The deduced protein structure contained nine zinc fingers, a proline-rich region, a nuclear bipartite localization signal, and a homeobox domain profile, suggesting a transcription factor function. Further comparative analysis identified an ADNP paralog (33% identity and 46% similarity), indicating that these genes belong to a novel protein family with a nine-zinc finger motif followed by a homeobox domain. The hADNP gene structure spans ϳ40 kilobases and includes five exons and four introns with alternative splicing of an untranslated second exon. The hADNP gene was mapped to chromosome 20q12-13.2, a region associated with aggressive tumor growth, frequently amplified in many neoplasias, including breast, bladder, ovarian, pancreatic, and colon cancers. hADNP mRNA is abundantly expressed in distinct normal tissues, and high expression levels were encountered in malignant cells. Down-regulation of ADNP by antisense oligodeoxynucleotides up-regulated the tumor suppressor p53 and reduced the viability of intestinal cancer cells by 90%. Thus, ADNP is implicated in maintaining cell survival, perhaps through modulation of p53.Mouse activity-dependent neuroprotective protein (mADNP), 1 a novel vasoactive intestinal peptide (VIP)-responsive gene, was recently cloned (1). The relative enrichment of mADNP transcripts in the cerebellum, cortex, hippocampus, medulla, and midbrain and the increases found in the presence of VIP, an established neuroprotective substance (2), implied a potential function in brain metabolism. Specifically, mADNP mRNA increased 2-3-fold in astroglial cells incubated for 3 h in the presence of nanomolar amounts of VIP (1). Another tissue containing increased mADNP transcripts is the mouse testis, a highly proliferative tissue, suggesting the involvement of ADNP in cell division.As deregulation of oncogenes has been associated with neurodegeneration (3), pathways that regulate neuronal survival may impinge upon cancer proliferation. VIP regulates both neuronal survival and cell division (2). A system whereby labeled VIP is suggested as a tumor marker has been proposed, localizing in vivo tumors of patients with gastrointestinal neuroendocrine cancers as well as pancreatic and colonic adenocarcinomas (4). Other studies have identified a very high incidence of VIP receptor binding in breast, ovarian, endometrial, prostate, bladder, lung, esophageal, colonic, and pancreatic tumors as well as in neuroendocrine and brain tumors (5). However, the VIP effect on cancer growth depends on the specific tumor and may be stimulatory (6, 7) or inhibitory (8). In view of the high incidence of tumors containing VIP receptors, a potential intervention in tumor growth may employ a gene downstr...

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The effect of oral supplementation of L-arginine, the substrate of nitric oxide, (1.25 g/liter water) and captopril (15 mg/liter water) was studied in 5/6 nephrectomized rats for a period of three months. N-omega-nitro L-arginine, a nitric oxide synthase inhibitor, was given orally (70 mg/liter water) with or without L-arginine or captopril. The urinary excretion of nitrite (NO2) + nitrate (NO3), the known metabolites of nitric oxide, was taken as an index of nitric oxide production. Chronic renal failure rats were characterized by a low creatinine clearance, high FENa%, proteinuria, hypertension and a low urinary excretion of NO2 + NO3; 0.152 +/- 0.06 (P < 0.001) nmol/micrograms creatinine compared with 0.481 +/- 0.004 (P < 0.001) in normal rats and 0.479 +/- 0.11 (P < 0.001) in untreated sham-operated rats. Both L-arginine and captopril were effective in the normalization of all these parameters. The combination of L-arginine and captopril had no additive effects. The nitric oxide synthase inhibitor significantly diminished the captopril beneficial effect. It is concluded that chronic renal failure in rats is a low nitric oxide production state. The supplementation of L-arginine is shown to overcome this condition. It is suggested that the beneficial effect of captopril on chronic renal failure is through a specific L-arginine--nitric oxide synthase--nitric oxide pathway.

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Many patients in our nephrology department who have anaemia and chronic kidney insufficiency (CKI) show evidence of congestive heart failure (CHF). This triad of anaemia, CKI and CHF is known as the cardio-renal anaemia syndrome. The three conditions form a vicious circle, in which each condition is capable of causing or being caused by another. Anaemia can increase the severity of CHF and is associated with a rise in mortality, hospitalization and malnutrition. Anaemia can also further worsen renal function and cause a more rapid progression to dialysis than is found in patients without anaemia. Uncontrolled CHF can cause rapid deterioration of renal function and anaemia. CKI can also cause anaemia, as well as worsen the severity of CHF, and is associated with increased mortality and hospitalization in patients with CHF. Aggressive therapy against CHF with all the conventional medications at the accepted doses often fails to improve the CHF if anaemia is also present but is not treated. In studies in which the anaemia was corrected with s.c. erythropoietin and, in some cases, with i.v. iron, however, the cardiac function improved, as assessed by measurement of the left ventricular ejection fraction and oxygen utilization during maximal exercise. Symptomatic patient functioning improved, as monitored by shortness of breath and fatigue on exertion, and the need for hospitalization and oral and i.v. diuretics markedly decreased. The quality of life, as judged by different criteria, also improved. The glomerular filtration rate, which fell rapidly when the anaemia was untreated, stabilized in patients when their anaemia was treated. Nephrologists need to assess the cardiac status of all patients with CKI carefully, and this includes an echocardiogram along with possibly measuring the levels of B-type natriuretic peptide. Nephrologists also need to use the indicated agents for CHF at the recommended doses, while cardiologists and internists need to be more aware of the importance and lethal effects of even mild anaemia and the benefits of its treatment in CHF and CKI. Cooperation between these specialists will allow better and much earlier treatment of the anaemia, CHF and CKI, and prevent the deterioration of all three conditions.