Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS.

Drug discovery in renal disease--towards a more efficient framework.

The time and cost involved in bringing new drugs to the market hamper their approval. This problem is especially apparent in the case of renal diseases. Efficient drug research requires an a priori understanding of disease pathophysiology, target validation, rational and efficient drug discovery strategies and early testing of the physiological and pharmacological effects of the new agent in humans.

Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration.

The prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT) depends on the rapid recovery and sustained life-long hematopoiesis. The activation of the fibrinolytic pathway promotes hematopoietic regeneration; however, the role of plasminogen activator inhibitor-1 (PAI-1), a negative regulator of the fibrinolytic pathway, has not yet been elucidated. We herein demonstrate that bone marrow (BM) stromal cells, especially osteoblasts, produce PAI-1 in response to myeloablation, which negatively regulates the hematopoietic regeneration in the BM microenvironment.

Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology?

The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent diabetic nephropathy (DN). Recently, a broad range of anomalies associated with oxygen biology, such as hypoxia, oxidative stress (OS), and dyserythropoiesis, have been implicated in DN. This review delineates the cellular mechanisms of these anomalies to pinpoint novel therapeutic approaches.

A small molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration.

Objective: Macrophage (Mϕ) migration rests on the adhesion/detachment between Mϕ surface components and extracellular matrixes, and the contribution of numerous inflammatory disorders. Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, influences Mϕ motility through an action distinct from its classical modulation of the plasmin-based fibrinolytic process. We rely here on a small molecule PAI-1 inhibitor (TM5275) to investigate the role of PAI-1 in Mϕ migration in the pathogenesis of renal injury.

New era for drug discovery and development in renal disease.

Drug discovery and development is a lengthy and expensive process. Testing new agents in humans at an early stage could reduce the time and costs involved in identifying drugs that are likely to succeed in clinical studies. New guidance has outlined the concept of exploratory clinical trials, which provide important information on a drug's distribution as well as its physiological and pharmacological effects in humans.

Hypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets.

A variety of human disorders, e.g., ischemic heart disease, stroke, kidney disease, eventually share the deleterious consequences of a common, hypoxic and oxidative stress pathway.

[The birth of nephrology in Brussels: P.-P. Lambert].

The career and scientific contributions of Professor P.-P. Lambert (1910-1999) are outlined.

Body weight control by a high-carbohydrate/low-fat diet slows the progression of diabetic kidney damage in an obese, hypertensive, type 2 diabetic rat model.

Obesity is one of several factors implicated in the genesis of diabetic nephropathy (DN). Obese, hypertensive, type 2 diabetic rats SHR/NDmcr-cp were given, for 12 weeks, either a normal, middle-carbohydrate/middle-fat diet (MC/MF group) or a high-carbohydrate/low-fat diet (HC/LF group). Daily caloric intake was the same in both groups.

A novel inhibitor of plasminogen activator inhibitor-1 provides antithrombotic benefits devoid of bleeding effect in nonhuman primates.

Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey).

Diabetic nephropathy: a disorder of oxygen metabolism?

Chronic hypoxia induces sequential abnormalities in oxygen metabolism (for example, oxidative stress, nitrosative stress, advanced glycation, carbonyl stress, endoplasmic reticulum stress) in the kidneys of individuals with diabetes. Identification of these abnormalities improves our understanding of therapeutic benefits that can be achieved with antihypertensive agents, the control of hyperglycemia and/or hyperinsulinemia and the dietary correction of obesity. Key to the body's defense against hypoxia is hypoxia-inducible factor, the activity of which is modulated by prolyl hydroxylases (PHDs)-oxygen sensors whose inhibition may prove therapeutic.

Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model.

Aim: Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria.

A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage.

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs' protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats.

A novel Sartan derivative with very low angiotensin II type 1 receptor affinity protects the kidney in type 2 diabetic rats.

Background: Antihypertensive angiotensin II receptor blockers (ARBs) protect the kidney, at least in part, independently of blood pressure lowering. Still, the extent to which blood pressure lowering is related to renoprotection remains unclear.

Methods And Results: 139 newly synthesized ARB-derivatives were assayed for inhibition of advanced glycation (AGEs).

The role of megsin, a serine protease inhibitor, in diabetic mesangial matrix accumulation.

In diabetic nephropathy decreased activities of matrix metalloproteinase (MMP)-2, MMP-9 and plasmin contribute to mesangial matrix accumulation. Megsin, a novel member of the serine protease inhibitor superfamily, is predominantly expressed in mesangial cells and is up-regulated in diabetic nephropathy and its overexpression spontaneously induces progressive mesangial expansion in mice. High-glucose stimulated megsin mRNA expression in an in vivo model of type II diabetic nephropathy as well as in vitro in cultured mesangial cells.

Reduction of albuminuria by angiotensin receptor blocker beyond blood pressure lowering: evaluation in megsin/receptor for advanced glycation end products/inducible nitric oxide synthase triple transgenic diabetic nephropathy mouse model.

Aim: Antihypertensive agents inhibiting the renin-angiotensin system (RAS), such as angiotensin II type 1 receptor blockers (ARB), are now part of the standard treatment of patients with diabetic nephropathy, regardless of the presence of systemic hypertension. Whether ARB achieve better renoprotection than other RAS-independent antihypertensive drugs has been an issue of controversy. Several lines of large clinical studies provided better renoprotection of ARB.

Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis.

Objective: Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Inhibition of serpins may prove therapeutic. As yet, however, only very few small molecule serpin inhibitors have been reported.

A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia.

We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5+/-18.

Cobalt ameliorates renal injury in an obese, hypertensive type 2 diabetes rat model.

Background: Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated.

A novel class of prolyl hydroxylase inhibitors induces angiogenesis and exerts organ protection against ischemia.

Objective: Hypoxia inducible factor (HIF) plays a pivotal role in the adaptation to ischemic conditions. Its activity is modulated by an oxygen-dependent hydroxylation of proline residues by prolyl hydroxylases (PHD).

Methods And Results: We discovered 2 unique compounds (TM6008 and TM6089), which inhibited PHD and stabilized HIF activity in vitro.

A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models.

Background: The reno- and cardiovascular-protective effects of angiotensin II receptor blockers (ARBs), have been ascribed, at least in part, to their ability to inhibit the formation of advanced glycation end products (AGEs), independently of their effect on blood pressure. They act through decreased oxidative stress, unlike previously reported AGE inhibitors which entrap reactive carbonyl (RCOs) precursors of AGEs. The hypotensive effects of ARBs', however, may limit their use.

Carbonyl stress reduction in peritoneal dialysis fluid: development of a novel high-affinity adsorption bead.

Objective: Heat sterilization of glucose peritoneal dialysis (PD) fluid generates reactive carbonyl compounds (RCOs), which have been implicated in the formation of advanced glycation end products (AGEs) on peritoneal proteins, with an attendant deterioration of peritoneal permeability in PD patients. To reduce their levels in PD fluid, we had previously devised beads coupled with RCO-trapping agents. The hazards linked to the diffusion of RCO-trapping compounds in the systemic circulation are avoided.

Bilateral nephrectomy in the 19th century. Uremic toxicity: from urea to potassium.

The paper describes potassium toxicity as it emerged in the 19th century following the studies of J.N. Comhaire (1778-1837), to these of V.