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)

Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Cyclooxygenase (COX)-derived prostanoids play important role in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly (PGI2) and PGE2 play critical roles in maintaining blood pressure and renal function in volume contracted states. Renal medullary COX2-derived prostanoids appear to have antihypertensive effect in individuals challenged with a high salt diet. 5-Lipoxygenase (LO)-derived leukotrienes are involved in inflammatory glomerular injury. LO product 12-hydroxyeicosatetraenoic acid (12-HETE) is associated with pathogenesis of hypertension, and may mediate angiotensin II and TGFbeta induced mesengial cell abnormality in diabetic nephropathy. P450 hydroxylase-derived 20-HETE is a potent vasoconstrictor and is involved in the pathogenesis of hypertension. P450 epoxygenase derived epoxyeicosatrienoic acids (EETs) have vasodilator and natriuretic effect. Blockade of EET formation is associated with salt-sensitive hypertension. Ceramide has also been demonstrated to be an important signaling molecule, which is involved in pathogenesis of acute kidney injury caused by ischemia/reperfusion, and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease.
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PMID:Physiologic and pathophysiologic roles of lipid mediators in the kidney. 1736 Nov 13

Small lipids such as eicosanoids exert diverse and complex functions. In addition to their role in regulating normal kidney function, these lipids also play important roles in the pathogenesis of kidney diseases. Increased glomerular cyclooxygenase (COX)1 or COX2 expression has been reported in patients with nephritis and in animal models of nephritis. COX inhibitors have shown beneficial effects on lupus nephritis and passive Heymann nephritis, but not anti-Thy1.1-induced nephritis. 5-Lipoxygenase-derived leukotrienes are involved in inflammatory glomerular injury. Lipoxygenase product 12-hydroxyeicosatetraenoic acid may mediate angiotensin II and transforming growth factor beta-induced mesangial cell abnormality in diabetic nephropathy. P450 arachidonic acid mono-oxygenase-derived 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids are involved in several forms of kidney injury, including renal injury in metabolic syndrome. Ceramide also has been shown to be an important signaling molecule that is involved in the pathogenesis of acute kidney injury caused by ischemia/reperfusion and toxic insults. Those pathways should provide fruitful targets for intervention in the pharmacologic treatment of renal disease.
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PMID:Roles of lipid mediators in kidney injury. 1753 10

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

Diabetes mellitus (DM) is a metabolic disorder with hyperglycemia being its hallmark symptom. The secondary symptom of DM is oxidative stress, which leads to the generation of free radicals. Diabetic nephropathy and neuropathy is the long-term effect of oxidative stress caused in DM, which leads to damage of kidneys and neurons respectively. Resveratrol (RES) is a phytochemical, found to be effective in the treatment of diabetic nephropathy and neuropathy. Due to its antioxidant property, it reduces the oxidative stress caused by DM. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 DM. In vitro and in vivo data depicted that the metabolism of alogliptin (ALO), saxagliptin (SAX) and sitagliptin (SIT) were decreased in presence of RES while metabolism of teneligliptin (TEN) was not affected in presence of RES. The results show that the alteration of the pharmacokinetics of ALO, SAX and SIT was due to inhibition of CYP P450 by RES. Thus, there was a significant pharmacokinetic interaction between RES-ALO, RES-SAX and RES-SIT. Hence, a dose reduction is required when RES therapy is taken in combination with ALO, SAX and SIT as there is an increase in drug exposure, which might lead to toxicity.
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PMID:Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach. 3178 86