Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morbidity and mortality of diabetes mellitus are strongly associated with cardiovascular disease including nephropathy. A discordant tissue renin-angiotensin system (RAS) might be a mediator of the endothelial dysfunction leading to both micro- and macrovascular complications of diabetes. The elevated plasma levels of prorenin in diabetic subjects with microvascular complications might be part of this discordant RAS, especially since the plasma renin levels in diabetes are low. Prorenin, previously thought of as an inactive precursor of renin, is now known to bind to a (pro)renin receptor, thus activating locally angiotensin-dependent and -independent pathways. In particular, the stimulation of the transforming growth factor-beta (TGF-beta) system by prorenin could be an important contributor to diabetic disease complications. This review discusses the concept of the prorenin-(pro)renin receptor-TGF-beta(1) axis, concluding that interference with this pathway might be a next logical step in the search for new therapeutic regimens to reduce diabetes-related morbidity and mortality.
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PMID:Diabetic complications: a role for the prorenin-(pro)renin receptor-TGF-beta1 axis? 1884 Apr 99

Hemodynamic stress in concert with metabolic pathways that are activated by hyperglycemia, glycated proteins, and oxidative stress induce a host of growth factors in the kidney. The fibrogenic cytokine transforming growth factor-beta (TGF-beta), through its Smad3 signaling pathway, is the etiologic agent of renal hypertrophy and the accumulation of mesangial extracellular matrix components in diabetes. Neutralizing anti-TGF-beta antibodies, antisense TGF-beta1 oligodeoxynucleotides or knocking off the Smad3 gene prevent and/or reverse the hypertrophic and profibrotic effects of the diabetic state in mice. However, there is limited evidence to support a role for TGF-beta in the development of albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is also increased in animal models of diabetic kidney disease, appears to act in a novel autocrine signaling mode to induce the podocytopathy of diabetes, especially the genesis of albuminuria. Future strategies for therapy of diabetic nephropathy may therefore need to involve interception of both the TGF-beta and the VEGF signaling pathways to counter the matrix accumulation and to improve the albuminuria. Interception of the renin-angiotensin system may achieve this goal but other novel strategies will need to be developed that would be more efficacious. However, a note of caution should be raised not to lower the heightened activities of these two signaling pathways much below normal levels because a basal activity for each is essential for the optimal homeostasis of glomerular cells.
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PMID:Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy. 1884 17

Amid the rapidly rising number of people with diabetes worldwide, the prevalence of diabetic kidney disease (DKD) is expected to increase considerably despite available treatments. Consequently, novel therapeutic agents are urgently needed. Ruboxistaurin mesylate is a bisindolylmaleimide that specifically inhibits the beta isoform of protein kinase C (PKC). In experimental models of DKD, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, preserved kidney function, and reduced mesangial expansion, glomerulosclerosis, and tubulointerstitial fibrosis. These beneficial effects of ruboxistaurin, both alone and combined with renin-angiotensin system inhibition, have been observed in a variety of experimental models of DKD. A phase 2 study of PKC-beta inhibition in persons with type 2 diabetes and DKD already treated with angiotensin converting enzyme inhibition and/or angiotensin receptor blockade has been conducted. Addition of ruboxistaurin for 1 year reduced urinary albumin, prevented an increase in urinary transforming growth factor-beta, and stabilized estimated glomerular filtration rate. Based on secondary analyses of clinical trials in patients with diabetic retinopathy or neuropathy, ruboxistaurin appears safe and may also prevent onset of DKD. PKC-beta inhibition holds promise as a new strategy to improve kidney disease outcomes in diabetes. Large-scale clinical trials will be required to confirm safety and to validate prospective benefits of ruboxistaurin on relevant clinical endpoints in DKD.
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PMID:Protein kinase C-beta inhibition for diabetic kidney disease. 1897 50

Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV), which results in dilation, eccentric hypertrophy, and eventually loss of function. Little is known about the impact of AR on LV gene expression. We, therefore, conducted a gene expression profiling study in the LV of rats with acute and severe AR. We identified 64 genes that were specifically upregulated and 29 that were downregulated out of 21,910 genes after 2 wk. Of the upregulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qRT-PCR) to see if the modulation seen in the LV after 2 wk persisted in the chronic phase (after 6 and 12 mo) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are overactivated in our animal model, we were interested to see if blocking those systems using metoprolol (25 mg.kg(-1).day(-1)) and captopril (100 mg.kg(-1).day(-1)) would alter the expression of some upregulated LV genes in AR rats after 6 mo. By qRT-PCR, we observed that upregulations of LV mRNA levels encoding for procollagens type I and III, fibronectin, atrial natriuretic peptide, transforming growth factor-beta(2), and connective tissue growth factor were totally or partially reversed by this treatment. These observations provide a molecular rationale for a medical strategy aiming these systems in the medical treatment of AR and expand the paradigm in the study of this form of LV volume overload.
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PMID:Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the beta-adrenergic and renin-angiotensin systems. 1911 94

In Japan, only about 3% of all patients with end-stage renal disease are maintained by continuous ambulatory peritoneal dialysis (CAPD). Although the reasons for the low proportion of patients receiving CAPD are multifactorial, encapsulating peritoneal sclerosis (EPS), a fatal complication of CAPD, is a major factor. In 1995 we developed a rat model of EPS, and in 2001 also developed an EPS model in mice. These rodent EPS models are reliable, reproducible, and inexpensive and have been used by other investigators. The renin-angiotensin system negatively regulates the transforming growth factor-beta signaling pathway, which plays a major role in tissue fibrosis. To investigate the anti-EPS effect of renin-angiotensin system inhibition, an angiotensin-converting enzyme inhibitor, quinapril, was administered to an EPS model in mice. Quinapril was found to inhibit EPS, both macro- and microscopically, in a dose-dependent manner. We report our experience of developing the experimental in vivo EPS model, and the inhibitory effect of this angiotensin-converting enzyme inhibitor on EPS.
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PMID:An experimental model of encapsulating peritoneal sclerosis. 1927 Feb 31

Substantial evidence demonstrates a link of increased plasminogen activator inhibitor-1 (PAI-1) and glomerulosclerosis and kidney fibrosis, providing a novel therapeutic option for prevention and treatment of chronic kidney diseases. Several mechanisms contributing to increased PAI-1 will be addressed, including classic key profibrotic factors such as the renin-angiotensin-system (RAS) and transforming growth factor-beta (TGF-b???and novel molecules identified by proteomic analysis, such as thymosin- b4. The fibrotic sequelae caused by increased PAI-1 in kidney depend not only on its classic inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA), but also its influence on cell migration.
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PMID:PAI-1 and kidney fibrosis. 1927 83

Type 2 Diabetes (T2D) is an important cause of renal dysfunction and the most common cause of end-stage renal disease (ESRD). Diabetic nephropathy is also associated with an increased risk of vascular disease and patient mortality. Aggressive management of hypertension to reduce microalbuminuria, together with tight glycaemic control are important therapeutic strategies for renal and vascular disease prevention in T2D. The main pathophysiological mechanisms associated with diabetic nephropathy result from activation of the renin-angiotensin-aldosterone system (RAAS), protein kinase C pathway, pro-inflammatory cytokines and various growth factors. Angiotensin II and transforming growth factor-beta (TGF-beta) are two important molecular mediators. The production of advanced glycation end-products (AGEs) and increased oxidative stress further exacerbates renal injury. These molecular changes within the renal tissue result in mesangial expansion, increased extracellular matrix deposition and an alteration in podocyte structure and function. Therapeutic targeting of these molecular pathways is an important area of translational research in diabetes. The elucidation of new genetic associations and proteomic biomarkers of diabetic kidney disease will also assist in the identification and treatment of high-risk patients. This review article will discuss both the molecular and clinical aspects of diabetic nephropathy, providing a bench-to-bedside research perspective to potential new therapeutic strategies.
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PMID:Therapeutic strategies in the treatment of diabetic nephropathy - a translational medicine approach. 1927 8

Animal and human studies support an untoward effect of excess dietary NaCl (salt) intake on cardiovascular and renal function and life span. Recent work has promoted the concept that the endothelium, in particular, reacts to changes in dietary salt intake through a complex series of events that are independent of blood pressure and the renin-angiotensin-aldosterone axis. The cellular signaling events culminate in the intravascular production of transforming growth factor-beta (TGF-beta) and nitric oxide in response to increased salt intake. Plasticity of the endothelium is integral in the vascular remodeling consequences associated with excess salt intake, because nitric oxide serves as a negative regulator of TGF-beta production. Impairment of nitric oxide production, such as occurs with endothelial dysfunction in a variety of disease states, results in unopposed excess vascular TGF-beta production, which promotes reduced vascular compliance and augmented peripheral arterial constriction and hypertension. Persistent alterations in vascular function promote the increase in cardiovascular events and reductions in renal function that reduce life span during increased salt intake.
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PMID:Vascular consequences of dietary salt intake. 1933 34

Glomerulosclerosis is characterized by mesangial matrix accumulation that is mediated primarily by activation of transforming growth factor-beta (TGF-beta). Unlike podocytes, mesangial cells secrete TGF-beta in response to common in vitro fibrogenic stimuli. However, mesangial immunostaining for active TGF-beta1 in chronic glomerular disease is almost negligible, despite increased mesangial TGF-beta1 mRNA expression, while podocytes covering the sclerotic glomerular segments exhibit increased TGF-beta1 protein expression. The mechanisms whereby TGF-beta is activated in the diseased glomeruli and how the activated TGF-beta leads to mesangial matrix overproduction are not clear. We provide evidence that TGF-beta secreted as latent complexes by mesangial cells is stored in the mesangial matrix, from which soluble forms of latent TGF-beta are released and localized to the podocyte surface in chronic glomerular disease. Podocyte-derived reactive oxygen species, plasmin and thrombospondin-1, particularly renin-angiotensin-aldosterone system-induced oxidative stress, seem to be involved in TGF-beta activation in podocytes. We also provide evidence that the TGF-beta-induced secretion of connective tissue growth factor and vascular endothelial growth factor by podocytes acts as a paracrine regulatory mechanism on mesangial cells, which may cause mesangial matrix accumulation culminating in the development of glomerulosclerosis. Collectively, these data bring new insights into our understanding of the roles of the mesangial cells and podocytes in the TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease.
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PMID:Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. 1947 36

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.
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PMID:Exaggerated blood pressure variability superimposed on hypertension aggravates cardiac remodeling in rats via angiotensin II system-mediated chronic inflammation. 1970 5


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