Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Losartan is the first orally available angiotensin-receptor antagonist without agonist properties. Following oral administration, losartan is rapidly absorbed, reaching maximum concentrations 1-2 hours post-administration. After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite. E 3174 is 10- to 40-fold more potent than its parent compound and its estimated terminal half-life ranges from 6 to 9 hours. The pharmacokinetics of losartan and E 3174 are linear, dose-proportional and do not substantially change with repetitive administration. The recommended dosage of losartan 50 mg/day can be administered without regard to food. There are no clinically significant effects of age, sex or race on the pharmacokinetics of losartan, and no dosage adjustment is necessary in patients with mild hepatic impairment or various degrees of renal insufficiency. Losartan, or its E 3174 metabolite, is not removed during haemodialysis. The major metabolic pathway for losartan is by the cytochrome P450 (CYP) 3A4, 2C9 and 2C10 isoenzymes. Overall, losartan has a favorable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between this drug and a range of inhibitors and stimulators of the CYP450 system. Losartan does not have a drug-drug interaction with hydrochlorothiazide, warfarin or digoxin. Losartan should be avoided in pregnancy, as is the case with all other angiotensin-receptor antagonists. When given in the second and third trimester of pregnancy, losartan is often associated with serious fetal toxicity. Losartan is a competitive antagonist that causes a parallel rightward shift of the concentration-contractile response curve to angiotensin-II, while E 3174 is a noncompetitive "insurmountable" antagonist of angiotensin-II. The maximum recommended daily dose of losartan is 100mg, which can be given as a once-daily dose or by splitting the same total daily dose into two doses. Losartan reduces blood pressure comparably to other angiotensin-receptor antagonists. Losartan has been extensively studied relative to end-organ protection, with studies having been conducted in diabetic nephropathy, heart failure, post-myocardial infarction and hypertensive patients with left ventricular hypertrophy. The results of these studies have been sufficiently positive to support a more widespread use of angiotensin-receptor antagonists in the setting of various end-organ diseases. Losartan, like other angiotensin-receptor antagonists, is devoid of significant adverse effects.
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PMID:Clinical pharmacokinetics of losartan. 1602 66

Curcumin (U1) has a wide spectrum of therapeutic effects such as antitumor and anti-inflammatory effects, including antibacterial, antiviral, antifungal, and antispasmodic activities. By comparison of the structure-activity relationship, tetrahydrocurcumin (THU1), one of the major metabolites, showed the highest antioxidative activity in both in vitro and in vivo systems. U1 has been reported to have the nephroprotective effect to improve creatinine and urea clearance and also protected the chronic renal allograft nephropathy. These beneficial effects have been explained by the protection of oxidative stress and the induction of antioxidative enzymes. The protective effect of THU1 against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage using male ddY mice was greater than that of U1, by monitoring not only radical scavenging activity measured by ESR, and TBARS, 4-HNE-modified protein and 8-OHdG formation but also induction of anioxidative enzymes and detoxification enzymes. THU1 was also expected to improve redox regulation through glutathione and suppress the oxidative stress in diabetic nephropathy and neuropathy. Earlier studies reported that U1 reduced the iron-induced hepatic damage, aflatoxin- and benzo[a]pyrene- induced mutagenicity and hepatocarcinogenecity and also the formation of the DNA adduct by inhibiting cytochrome P450 in the liver. The hepatoprotective role of U1 has been examined using carbone terachloride-induced liver damage in rats and alcoholic liver disease model rats, but not examined using THU1. Our recent data suggests that THU1 is a more promising hepatprotective agent because of its strong induction activity of antioxidant and phase 2-metabolizing enzymes in liver compared to kidney, although more detaied examinations are required.
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PMID:Nephroprotective and hepatoprotective effects of curcuminoids. 1756 22

Pathological angiogenesis is a key feature of many diseases including retinopathies such as ROP (retinopathy of prematurity) and DR (diabetic retinopathy). There is considerable evidence that increased production of ROS (reactive oxygen species) in the retina participates in retinal angiogenesis, although the mechanisms by which this occurs are not fully understood. ROS is produced by a number of pathways, including the mitochondrial electron transport chain, cytochrome P450, xanthine oxidase and uncoupled nitric oxide synthase. The family of NADPH oxidase (Nox) enzymes are likely to be important given that their primary function is to produce ROS. Seven isoforms of Nox have been identified named Nox1-5, Duox (dual oxidase) 1 and Duox2. Nox1, Nox2 and Nox4 have been most extensively studied and are implicated in the development of conditions such as hypertension, cardiovascular disease and diabetic nephropathy. In recent years, evidence has accumulated to suggest that Nox1, Nox2 and Nox4 participate in pathological angiogenesis; however, there is no clear consensus about which Nox isoform is primarily responsible. In terms of retinopathy, there is growing evidence that Nox contribute to vascular injury. The RAAS (renin-angiotensin-aldosterone system), and particularly AngII (angiotensin II), is a key stimulator of Nox. It is known that a local RAAS exists in the retina and that blockade of AngII and aldosterone attenuate pathological angiogenesis in the retina. Whether the RAAS influences the production of ROS derived from Nox in retinopathy is yet to be fully determined. These topics will be reviewed with a particular emphasis on ROP and DR.
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PMID:Reactive oxygen species, Nox and angiotensin II in angiogenesis: implications for retinopathy. 2337 42

Diabetic nephropathy (DN) is one of the most serious complications of type I and type II diabetes. DN is characterized by hyperfiltration, hypertrophy, extracellular matrix accumulation, and proteinuria. This advances into renal fibrosis and loss of renal function. Reactive oxygen species (ROS) and TGF-beta have been implicated in the pathogenesis of diabetic nephropathy. Early stages of diabetic nephropathy are also associated with alterations in renal sodium handling as well as hypertension; both are processes linked by involvement of the arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE, produced by cytochrome P450-4a, (CYP4A) and epoxyeicosatrienoic acids (EETs). Indeed, metabolism of AA is increased in a rat model of diabetes. In this study, we demonstrate that rats with streptozotocin-induced diabetes of 1 month duration develop renal hypertrophy and increased fibronectin and TGF-beta1 expression/cortical levels concomitant with an increase in CYP4A expression and 20 HETE production. These results were also paralleled by an increase in reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of diabetic rats with HET0016, selective inhibitor of CYP 4A, prevented all these changes. Our results suggest that diabetes-induced induction of CYP4A and 20-HETE production could be a major pathophysiological mechanism leading to activation of ROS through an NADPH dependent pathway and TGF-beta1 thus resulting in major renal pathology. Inhibitors of 20-HETE production could thus have an important therapeutic potential in the treatment of diabetic nephropathy.
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PMID:Involvement of renal cytochromes P450 and arachidonic acid metabolites in diabetic nephropathy. 2415 38

In the kidney, 20-hydroxyeicosatetraenoic acid (20-HETE) is a primary cytochrome P450 4 (Cyp4)-derived eicosanoid that enhances vasoconstriction of renal vessels and induces hypertension, renal tubular cell hypertrophy, and podocyte apoptosis. Hypertension and podocyte injury contribute to diabetic nephropathy and are strong predictors of disease progression. In this study, we defined the mechanisms whereby 20-HETE affects the progression of diabetic nephropathy. We used Cyp4a14KO male mice that exhibit androgen-sensitive hypertension due to increased Cyp4a12-mediated 20-HETE production. We show that, upon induction of diabetes type 1 via streptozotocin injection, Cyp4a14KO male mice developed worse renal disease than streptozotocin-treated wild-type mice, characterized by increased albuminuria, mesangial expansion, glomerular matrix deposition, and thickness of the glomerular basement membranes. Castration blunted androgen-mediated Cyp4a12 synthesis and 20-HETE production, normalized BP, and ameliorated renal damage in diabetic Cyp4a14KO mice. Notably, treatment with a 20-HETE antagonist or agents that normalized BP without affecting Cyp4a12 expression and 20-HETE biosynthesis also ameliorated diabetes-mediated renal damage and albuminuria in Cyp4a14KO male mice. Taken together, these results suggest that hypertension is the major contributor to 20-HETE-driven diabetes-mediated kidney injury.
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PMID:Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. 2507 Oct 86

Human cytochrome P450 (P450) 11B2 catalyzes the formation of aldosterone, the major endogenous human mineralocorticoid. Aldosterone is important for the regulation of electrolyte homeostasis. Mutations and overexpression of P450 11B2 (also known as aldosterone synthase) can lead to hypertension, congestive heart failure, and diabetic nephropathy. The enzyme is therefore a target for drug development to manage these various disorders. P450 11B2 catalyzes aldosterone formation from 11-deoxycorticosterone through three distinct oxidation steps. It is currently unknown to which degree these reactions happen in sequence without the intermediate products dissociating from the enzyme (i.e. processively) or whether these reactions happen solely distributively, in which the intermediate products must first dissociate and then rebind to the enzyme before subsequent oxidation. We present here a comprehensive investigation of processivity in P450 11B2-catalyzed reactions using steady-state, pre-steady-state, pulse-chase, equilibrium-binding titrations, and stopped-flow binding studies. We utilized the data obtained to develop a kinetic model for P450 11B2 and tested this model by enzyme kinetics simulations. We found that although aldosterone is produced processively, the enzyme preferentially utilizes a distributive mechanism that ends with the production of 18-OH corticosterone. This seemingly contradictory observation could be resolved by considering the ability of the intermediate product 18-OH corticosterone to exist as a lactol form, with the equilibrium favoring the ring-closed lactol configuration. In summary, our refined model for P450 11B2 catalysis indicates isomerization of the intermediate to a lactol can explain why P450 11B2 must produce aldosterone through a processive mechanism despite favoring a distributive mechanism.
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PMID:Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone. 3129 61