Showing papers by "Mark E. Cooper published in 2006"

Connective Tissue Growth Factor Plays an Important Role in Advanced Glycation End Product–Induced Tubular Epithelial-to-Mesenchymal Transition: Implications for Diabetic Renal Disease

Abstract: Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-β1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of α-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-β1 antibodies, suggesting that this action was TGF-β1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 μM) or TGF-β1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-β1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-β1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy.

Changes in drought tolerance in maize associated with fifty years of breeding for yield in the US Corn Belt [Zea mays L.]

Abstract: Understanding the changes underlying past breeding progress may help to focus research efforts and accelerate future genetic gains. The major abiotic stress affecting maize production on a worldwide basis is drought. We addressed the improvements in drought tol- erance over a 50-year period of hybrid breeding by evalu- ating, under targeted stress conditions, a set of 18 Pio- neer-brand hybrids that had been released during the 1953-2001 period. Stress treatments were designed as overlapping windows of water deficit covering the pre- flowering to late grain filling development stages. Data were collected on grain yield, yield components and an- thesis-silking interval (ASI), and were analyzed using a linear mixed model approach. Genetic gain was mea- sured as the slope of the regression of the trait on the year of hybrid release. Significant, positive genetic gains of varying magnitude were observed for grain yield in all windows of stress evaluated. The largest genetic gains for grain yield were observed under conditions of full irriga- tion and severe flowering stress. ASI and barrenness, es- pecially under stress at flowering, were significantly re- duced by selection. Though flowering remains the most susceptible stage to drought in maize, selection has re- duced its negative effects, and susceptibility during early grain filling is now of similar importance in many modern hybrids. Yield under drought at flowering has more than kept pace with the increase in yield potential because of the emphasis breeders have placed on improved floral synchrony.

Mechanisms of diabetic nephropathy: role of hypertension.

Abstract: Diabetic nephropathy is a major microvascular complication of diabetes, representing the leading cause of end-stage renal disease in the Western world, and a major cause of morbidity and mortality in both type 1 and type 2 diabetic subjects. Clinical hallmarks of diabetic nephropathy include a progressive increase in urinary albumin excretion and a decline in glomerular filtration rate (GFR), which occur in association with an increase in blood pressure, ultimately leading to end-stage renal failure.1 These renal functional changes develop as a consequence of structural abnormalities, including glomerular basement membrane thickening, mesangial expansion with extracellular matrix accumulation, changes in glomerular epithelial cells (podocytes), including a decrease in number and/or density, podocyte foot process broadening and effacement, glomerulosclerosis, and tubulointerstitial fibrosis. Diabetic nephropathy occurs only in a minority of subjects with either type 1 or type 2 diabetes and seems to result from the interaction between genetic susceptibility and environmental insults, primarily metabolic and hemodynamic in origin. Over the last decade, the cellular and molecular mechanisms by which these insults translate to structural and functional abnormalities leading to diabetic nephropathy have been increasingly delineated. In particular, it has been determined that both metabolic and hemodynamic stimuli lead to the activation of key intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines, and growth factors, which mediate and/or amplify renal damage. In the present review, we summarize molecular and cellular mechanisms that seem to be responsible for hypertension-induced renal injury in diabetes, with particular focus on the role of increased intracapillary glomerular pressure, more recently discovered components of the renin–angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) 2, and the increasing knowledge that has been gained emphasizing cross-talk between metabolic and hemodynamic pathways in amplifying diabetes-related renal injury. The relationship between hypertension and poor vascular outcomes, including …

The burden of chronic kidney disease in Australian patients with type 2 diabetes (the NEFRON study).

Abstract: Objective: To estimate the frequency of chronic kidney disease (CKD) in a clinic-based sample of patients with type 2 diabetes in the setting of Australian primary care. Design, setting and participants: Expressions of interest were invited from all registered general practitioners in Australia: 500 GP investigators were randomly selected from each stratum (state and urban versus rural location), proportional to the census population, and asked to recruit and provide data for 10–15 consecutively presenting adults with type 2 diabetes between April and September 2005. Main outcome measures: Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m 2 and evidence of kidney damage on urinalysis (eg, microalbuminuria). Results: 348 GP investigators submitted data for 3893 individuals with type 2 diabetes (52% men; median age, 66 years). Almost one in every four patients consulting their GPs had an eGFR < 60 mL/min/1.73 m 2 (23.1%; 95% CI, 21.8%–24.5%). More than one in three had an elevated urinary albumin–creatinine ratio (ACR) (34.6%; 95% CI, 33.3%–35.9%). There was an overlap of 10.4% of patients with both an eGFR < 60 mL/min/1.73 m 2 and an elevated urinary ACR, meaning that almost one in two patients with type 2 diabetes consulting their GPs (47.1%; 95% CI, 45.8%–48.4%) had CKD. CKD was significantly more common in women, in older people, and in individuals with established macrovascular disease. Conclusion: CKD is a common complication of type 2 diabetes, found in about half of all patients with type 2 diabetes consulting their GPs. Efforts to increase the recognition

PPAR-α and -γ agonists attenuate diabetic kidney disease in the apolipoprotein E knockout mouse

Abstract: Backgound. Peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-a agonist, gemfibrozil, the PPAR-g agonist rosiglitazone and the non-thiazolidinedione PPAR-a/g coagonist, compound 3q, on kidney structure and function in streptozotocin-treated apolipoprotein E knockout mice. Methods. Control and streptozotocin-diabetic mice were randomized to receive rosiglitazone (20 mg/kg/ day), gemfibrozil (100 mg/kg/day), or compound 3q (3 mg/kg/day) by gavage, or no treatment for a period of 20 weeks. Renal fibrosis was assessed by standard histology and collagen IV immunohistochemistry. Kidney function was assessed by urinary albumin excretion and creatinine clearance. Results. Diabetes in this model was associated with an increase in glomerulosclerosis, tubulointerstitial fibrosis and increased collagen IV deposition in the glomeruli and tubules. All three agents significantly attenuated glomerulosclerosis, tubulointerstitial expansion and collagen IV deposition. The increase in albuminuria and the decline in kidney function associated with diabetes in this model were also attenuated by each of these agents, with no superiority observed among various treatment groups. These renoprotective effects were observed in the absence of changes in glucose, insulin or lipid levels or a reduction in blood pressure. Conclusions. Combined with their independent antiatherosclerotic actions, and their important effects on dyslipidaemia and insulin resistance, PPAR agonists may be useful for the prevention of diabetic complications, including kidney disease, even in type 1 diabetes.

Serum lipids and the progression of nephropathy in type 1 diabetes.

Abstract: OBJECTIVE —Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS —A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8–9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS —In patients with normoalbuminuria ( n = 66), progression was associated with male sex ( P P = 0.02), and LDL-free cholesterol ( P = 0.02). In patients with microalbuminuria ( n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P n = 36), a significant decline in the renal function (>3 ml · min −1 · year −1 ) was independently associated with poor glycemic control, hypertension, and LDL size ( P P CONCLUSIONS —Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.

Anaemia in diabetes: is there a rationale to TREAT?

Abstract: Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden. Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3–4 nephropathy. It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

Abstract: It is postulated that peroxisome proliferator-activated receptor α agonists confer cardiovascular benefits in diabetes, independently of their effects on lipid metabolism. We investigated putative mechanisms responsible for these anti-atherogenic effects in an in vivo model of diabetes-associated atherosclerosis. Control and streptozotocin-induced diabetic apolipoprotein-deficient mice received gemfibrozil (100 mg kg−1 day−1) or no treatment for 20 weeks. Aortic plaque deposition was assessed by Sudan IV staining and subsequent en face quantification. Superoxide production was measured using lucigenin-enhanced chemiluminescence. Markers of pathways including inflammation and oxidative stress were measured using real-time RT-PCR. No significant effect of gemfibrozil was observed on glycated haemoglobin, cholesterol or insulin in diabetic mice. Diabetes was associated with a three-fold increase in plaque area and a significant increase in NADPH-dependent superoxide compared with control mice. Gemfibrozil significantly attenuated plaque area and superoxide production in diabetic mice. In addition, gemfibrozil reduced the expression of the genes encoding the NADPH oxidase subunits p47phox, gp91phox and Rac-1. In addition, gemfibrozil reduced the expression of the genes encoding nuclear factor kappa B (NF-κB) subunit, p65, the NF-κB-dependent chemokine monocyte chemoattractant protein-1, and tissue factor. This study demonstrates that gemfibrozil exerts anti-atherogenic actions, independently of changes in cholesterol and glucose metabolism. Such findings emphasise the possible usefulness of fibrates such as gemfibrozil in a setting of atherosclerosis even in the absence of dyslipidaemia.

Diabetic nephropathy: from mechanisms to rational therapies.

Abstract: Diabetic nephropathy is a microvascular complication of diabetes. Specifically, it represents a major cause of morbidity and mortality in type 1 and type 2 diabetic subjects and has become the leading cause of end-stage renal disease in the Western world. Diabetic nephropathy appears to develop as a result of interactions between environmental insults and genetic susceptibility. Indeed, hyperglycemia is a clinical prerequisite for this complication, but it should be noted that only a subset of diabetic subjects will ultimately develop nephropathy. Over recent decades, cellular and molecular mechanisms underlying diabetic nephropathy have been increasingly delineated. In particular, diabetic kidney disease appears to occur as a result of the deleterious effects of both metabolic and hemodynamic insults, which at the cellular level lead to the activation of intracellular signaling pathways and transcription factors, thus triggering the production/release of cytokines, chemokines and growth factors, which mediate and/or amplify the renal damage. This ultimately leads to the structural and functional features characteristic of diabetic kidney disease. In the present review we summarize the evidence for key mediators of injury, which appear to be excellent treatment targets in diabetic nephropathy. The targets include various vasoactive hormones, the biochemical processes of the advanced glycation and protein kinase C. Furthermore, we review current and potentially new renoprotective therapies in the setting of diabetes.

Efficacy and Safety of Angiotensin II Receptor Blockade in Elderly Patients With Diabetes

Abstract: OBJECTIVE —While national guidelines recommend ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy in patients with diabetes and nephropathy, guidelines concerning elderly patients with diabetes have not endorsed these drugs. We sought to assess the nephroprotective efficacy and safety of ARB therapy in elderly patients by conducting age-specific subgroup analyses using data from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. RESEARCH DESIGN AND METHODS —We studied 1,513 patients with type 2 diabetes and nephropathy who randomly received either losartan or placebo. We tested for effect modification by age of the effect of losartan on the incidence of the predefined end points (doubling of serum creatinine, end-stage renal disease [ESRD], or death) and the risk of adverse events. RESULTS —Of 1,513 participants, 421 (27.8%) were aged >65 years (maximum age 74 years). Age did not modify the efficacy of losartan in reducing the risk of the primary outcome, a composite of doubling of serum creatinine, ESRD, or death ( P interaction = 0.66) or its individual components (all P interaction > 0.44). In patients aged >65 years, losartan reduced the risk of ESRD by 50% (95% CI 30–81, P = 0.005). We found no evidence that older patients were more likely to experience adverse events from losartan such as a rise in serum creatinine or hyperkalemia than younger patients. CONCLUSIONS —Elderly patients had the same level of benefits and risks as younger patients from treatment with losartan. Underuse of ACEI and ARB therapy in elderly patients because of the perceived lack of efficacy or a greater risk of adverse events appears unjustified.

Preventing diabetes in patients with hypertension: one more reason to block the renin-angiotensin system.

Abstract: Patients with essential hypertension are at increased risk of type 2 (non-insulin-dependent) diabetes. Recent large studies have been unable to delineate any superiority in one class of antihypertensive drug over another, independent of their effects in reducing blood pressure; however, in the longer term, antihypertensive agents that are able to reduce the risk of diabetes may have a theoretical advantage. To this end, the findings of several recent clinical trials have suggested that blockade of the renin-angiotensin system (RAS) may protect against the development of de-novo diabetes in 'at risk' patients. This beneficial effect appears to outweigh both the adverse metabolic effects of agents used in the control arm of these studies and the control of blood pressure achieved. Furthermore, recent evidence suggests that the RAS may have a direct role in the pathogenesis of diabetes. Angiotensin-mediated increases in oxidative stress, inflammation, and free fatty acids concentrations potentially contribute to beta-cell dysfunction in diabetes. In addition, activation of the RAS appears to potentiate the action of other pathogenic pathways, including glucotoxicity, lipotoxicity, and advanced glycation. In experimental models of type 2 diabetes, blockade of the RAS with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists also results in the improvement of islet structure and function. At least three large controlled trials are currently under way to study the utility of blockade of the RAS in the development of diabetes, including studies of combination therapy. It is hoped that these studies will demonstrate the true potential of blockade of the RAS for the prevention of diabetes.

Current biosensor technologies in drug discovery

Abstract: Over the past two decades the benefits of biosensor analysis have begun to make an impact in the market, and systems are beginning to be used as mainstream research tools in many laboratories1,2. Biosensors are devices that use biological or chemical receptors to detect analytes in a sample.They give detailed information on the binding affinity, and in many cases also the binding kinetics of an interaction.Typically, the receptor molecule must be connected in some way to a transducer that produces an electrical signal in real-time. Labelfree biosensors do not require the use of reporter elements (fluorescent, luminescent, radiometric, or colorimetric) to facilitate measurements. Detailed information on an interaction can be obtained during analysis while minimising sample processing requirements and assay run times3. Unlike label- and reporter-based technologies that simply confirm the presence of the detector molecule, label-free techniques can provide direct information on analyte binding to target molecules typically in the form of mass addition or depletion from the surface of the sensor substrate, or measuring changes in the heat capacity of a sample4. However, these technologies have failed to gain widespread acceptance due to technical constraints, low throughput, high user expertise requirements, and cost.While they can be powerful tools in the hands of a skilled user evaluating purified samples, they are not readily adapted to every day lab use where simple to understand results on high numbers of samples are the norm.This article seeks to address some of the issues surrounding the un-met needs in the market place, and the difficulties faced by technology developers in meeting these needs with innovative products. It also reviews recent entries from newer technology developers who are in the race to release products for primary and secondary drug screening, mode of action studies, and screening of pharmacokinetic properties.

Renal microvascular injury in diabetes: RAGE and redox signaling

Abstract: Diabetic nephropathy remains a major cause of morbidity and mortality in the diabetic population and is the leading cause of end-stage renal failure in the Western World. Despite current therapeutics including intensified glycemic control and blood pressure lowering agents, renal disease continues to progress relentlessly in diabetic patients, albeit at a lower rate. It is well recognized that metabolic and hemodynamic factors play a central role in accelerating renal disease in diabetes. However, recent experimental studies have suggested that increased generation of reactive oxygen species (ROS) as a result of the diabetic milieu may play a central role in the progression of diabetic microvascular complications. These ROS appear to be generated primarily from mitochondrial sources and via the enzyme, NADPH oxidase. This review focuses on how ROS play a deleterious role in the diabetic kidney and how they are involved in crosstalk among various signaling pathways, ultimately leading to renal dysfunction and structural injury.

Advanced glycation end products and vascular structure and function.

Abstract: Diabetes mellitus has now reached epidemic proportions in the Western world. The associated microvascular and macrovascular complications are a result of severe metabolic derangement, which leads to chronic tissue injury. Although there are a number of proposed pathophysiologic mechanisms for the vascular complications associated with diabetes, this review focuses predominantly on the role of advanced glycation end products (AGEs) in the pathogenesis of diabetes-associated atherosclerosis. The potential role of AGEs in enhancing arterial stiffness, an entity occurring with a greater prevalence in populations known to have higher-than-normal AGE levels, is also examined. Pharmacologic interventions aimed at reducing the level of these chemical compounds or interrupting their action provide hope for the future treatment of both atherosclerotic vascular disease and systolic hypertension, particularly in the setting of diabetes.

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes: a subanalysis of Japanese patients from the RENAAL study.

Abstract: Background The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation.

Advanced Glycation End Products Inhibit Tubulogenesis and Migration of Kidney Epithelial Cells in an Ezrin-Dependent Manner

Abstract: Nonenzymatic glycation of proteins to form advanced glycation end products (AGE) is implicated in diabetic complications, including nephropathy. It was shown recently that AGE bind to the ERM (ezrin, radixin, and moesin) family of membrane-cytoskeletal linker proteins in renal homogenates. Herein is reported the effects of AGE-BSA on ezrin-dependent LLC-PK1 kidney epithelial cellular functions: migration and hepatocyte growth factor (HGF)-induced tubulogenesis. LLC-PK1 cells were stably transfected with cDNA for ezrin sense, ezrin antisense, and N-ezrin. Transfection of LLC-PK1 cells with ezrin antisense and dominant negative N-ezrin decreased basal tubulogenesis and migration relative to vector-only transfection, establishing the ezrin dependency of these processes. AGE-BSA (20 or 40 microM) significantly decreased HGF-induced tubulogenesis and basal migration in two vector control lines relative to BSA-treated cells. However, AGE-BSA inhibition of both HGF-induced tubulogenesis and migration was overcome by overexpressing ezrin. These results demonstrate that the AGE-ezrin interaction significantly alters cellular function. These changes may be relevant to detrimental renal consequences as a result of diabetes.

Quantification of small molecule-receptor affinities and kinetics by acoustic profiling.

Abstract: The label-free RAP♦id 4™ system that exploits resonant acoustic profiling (RAP™) from Akubio (Cambridge, UK) was used to determine the affinity and kinetics for several different small molecule–receptor interactions. This was achieved by attaching the target receptor to the surface of quartz crystal resonators through a variety of specific coupling chemistries, followed by application of a small-molecular-weight ligand to the receptor via a microfluidic flow-based delivery system. Rank order of binding was determined for very weak interactions such as cofactor binding to glucose dehydrogenase. Moderate interaction affinities and binding kinetics could be determined for biotin binding to a specific antibody, and also for several low-molecular-weight sulfonamide analogues binding to human carbonic anhydrase isoform II. The equilibrium binding constants were in general agreement with the values obtained by kinetic analysis of the data, as well as with previously published values obtained using surface plasmo...

Genetic diversity among maize hybrids widely grown in contrasting regional environments in the United States during the 1990s

Abstract: Geographic regions can be classified accord- ing to broad parameters of climatic conditions that can be expected from historical data. Biotic and abiotic stress conditions that cultivated varieties will encounter depend in large part upon climatic conditions. Genetic diversity ar- rayed within cultivars might therefore be expected to vary across geographic regions and to be associated with differ- ent climates. Our goals were therefore to utilize pedigree data to examine the extent and patterns of genetic diversi- ty among maize hybrids that were widely cultivated dur- ing the 1990s in each of ten U.S. states that collectively represent contrasting climatic conditions. Forty-eight hy- brids were selected on the basis that they represented the ten most widely grown hybrids in each of ten states for which pedigree data were available to us. The hybrids had 53 founders. Patterns of genetic diversity among hybrids were associated with climatic differences among regions. Multivariate analysis of pedigree data clustered states into four groups that reflected their contrasting climates. Most founders showed differences in their pedigree contribu- tions to hybrids among different regions. Abilities of breeders and farmers to access a base of genetic diversity are necessary to allow continued adaptation of improved varieties and to help provide insurance against crop failure associated with inclement weather, pests or diseases.

Management Strategies for Patients With Hypertension and Diabetes: Why Combination Therapy Is Critical

Abstract: Hypertension is commonly associated and acts synergistically with diabetes in increasing the risk of macrovascular and microvascular diabetic complications. Large-scale clinical trials have demonstrated that this risk is significantly reduced by intensive antihypertensive treatment, and accordingly, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guideline has further lowered the blood pressure goals for diabetic subjects to <130/80 mm Hg. This implies that most diabetic patients will require the combination of two or more antihypertensive agents to achieve this blood pressure target. Although the most effective combination strategy in diabetes has not yet been determined in large-scale randomized clinical trials, a combination that includes at least one agent that interrupts the renin-angiotensin system appears to not only have a good safety profile, but may also provide additional renal and cardiovascular protection. Other antihypertensive agents should be added based on the patients risk profile and overall treatment regimen to achieve blood pressure goal.

Angiotensin receptor blockers and the kidney: possible advantages over ACE inhibition?

Abstract: This review deals with similarities and differences between the effects of ACE inhibitors and AT1-receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1 blockers arise from two mechanisms: the reduction of the AT1 receptor mediated response and the increase in plasma levels of Ang II through the AT1-receptor blockade, which leads to increased stimulation of the AT2 receptor (the so-called yin-yang effect). Both ACE inhibition and AT1-receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1 receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1-receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long-term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.