Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At present, diabetic kidney disease affects about 15-25 % of patients with type 1 diabetes (T1D) and 30-40 % of patients with type 2 diabetes (T2D). Several decades of extensive research have elucidated various pathways to be implicated in the development of diabetic kidney disease. These include metabolic factors beyond blood glucose (e.g. advanced glycation endproducts (AGEs)), haemodynamic factors (e.g. the renin angiotensin system (RAS)), intracellular signaling molecule proteins (e.g. protein kinase C (PKC)) and growth factors/cytokines (e.g. growth hormone (GH), insulin-like growth factors (IGFs), transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF)). This review focuses on the role of three of these growth factors, i.e. GH, IGFs and VEGF. A brief discussion of each system is followed by description of its expression in the normal kidney. Then, for each system, in vitro, experimental and clinical evidence addressing the role of the system in diabetic kidney disease is presented. The interplay of each system to other potential pathways will also be addressed. Finally, well-known and potential therapeutic strategies targeting the GH/IGF and VEGF systems in a specific or indirect way will discussed.
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PMID:The involvement of growth hormone (GH), insulin-like growth factors (IGFs) and vascular endothelial growth factor (VEGF) in diabetic kidney disease. 1554 23

At present, diabetic kidney disease affects about 15-25% of type 1 and 30-40% of type 2 diabetic patients. Several decades of extensive research has elucidated various pathways to be implicated in the development of diabetic kidney disease. This review focuses on the metabolic factors beyond blood glucose that are involved in the pathogenesis of diabetic kidney disease, i.e., advanced glycation end-products and the aldose reductase system. Furthermore, the contribution of hemodynamic factors, the renin-angiotensin system, the endothelin system, and the nitric oxide system, as well as the prominent role of the intracellular signaling molecule protein kinase C are discussed. Finally, the respective roles of TGF-beta, GH and IGFs, vascular endothelial growth factor, and platelet-derived growth factor are covered. The complex interplay between these different pathways will be highlighted. A brief introduction to each system and description of its expression in the normal kidney is followed by in vitro, experimental, and clinical evidence addressing the role of the system in diabetic kidney disease. Finally, well-known and potential therapeutic strategies targeting each system are discussed, ending with an overall conclusion.
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PMID:From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. 1558 25

We reported previously that insulin inhibits the stimulatory effect of high glucose on the expression of angiotensinogen (ANG) gene in both rat immortalized renal proximal tubular cells (IRPTCs) and non-diabetic rat renal proximal tubular cells (RPTCs), but has no effect in diabetic rat RPTCs. In the present study we investigated whether hyperglycaemia-induced resistance to the insulin-induced inhibition of expression of the ANG gene is mediated via the generation of reactive oxygen species (ROS) in RPTCs. Rat IRPTCs were cultured for 2 weeks in high-glucose (25 mM) or normal-glucose (5 mM) medium plus angiotensin II (Ang II) with or without a superoxide scavenger (tiron), or inhibitors of: NADPH oxidase (diphenylene iodinium, DPI), Ang II type 1 and 2 receptors (losartan and PD123319), angiotensin-converting enzyme (perindopril), protein kinase C (GF 109203X), or glutamine:fructose-6-phosphate amino-transferase (azaserine). Cellular generation of ROS, and ANG and renin mRNA levels were assessed by lucigenin assay and specific reverse transcriptase-PCR respectively. Phosphorylation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) was evaluated by western blotting. Prolonged exposure of IRPTCs to high concentrations of glucose or Ang II evoked generation of ROS and resistance to the insulin-induced inhibition of expression of the ANG gene and of p44/42 MAPK phosphorylation. Co-incubation of IRPTCs with tiron, DPI, losartan, PD123319, perindopril, GF 109203X or azaserine prevented ROS generation, restoring the inhibitory action of insulin on ANG gene expression and on p44/42 MAPK phosphorylation. In conclusion, our studies demonstrate that blockade of both ROS generation and activation of the intrarenal renin-angiotensin system improves the inhibitory action of insulin on ANG gene expression in IRPTCs in conditions of high glucose.
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PMID:Reactive oxygen species blockade and action of insulin on expression of angiotensinogen gene in proximal tubular cells. 1559 Sep 80

Myocardial cell death is an important contributor to the development of diabetic cardiomyopathy. It has been proposed that diabetes-mediated upregulation of the renin-angiotensin system leads to oxidative stress, the trigger for cardiomyocyte death and contractile dysfunction. However, the adverse effect of ANG II on the diabetic heart may extend beyond the development of the cardiomyopathy. ANG II also alters specific modulators of ischemic injury, such as PKC and calcium transport. Therefore, the present study examined the effect of ANG II on hyperglycemic preconditioning, a glucose-mediated condition associated with the elevation of PKC activity and alterations in calcium transport that render the cell resistant to hypoxia. Exposure of the glucose-treated cell to ANG II during the prehypoxic period blocked glucose-mediated cardioprotection. The reversal of hyperglycemic preconditioning was associated with enhanced accumulation of Ca(2+) during hypoxia, an effect prevented by inhibition of the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. The inhibitors of hypoxia-mediated Ca(2+) accumulation also blocked the reversal of hyperglycemic preconditioning by ANG II. Thus ANG II and glucose treatment exert opposite actions on the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. Because those transporters are involved in hypoxia-mediated apoptosis, they are logical candidates for the beneficial effects of high glucose and the adverse effects of ANG II on the hypoxic cardiomyocyte.
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PMID:Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport. 1560 29

Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processes are interwoven and present two sides of one coin. On a molecular level, hyperglycaemia and proteins altered by high blood glucose such as Amadori products and advanced glycation end-products (AGEs) are key players in the development of diabetic nephropathy. Recent evidence suggests that an increase in reactive oxygen species (ROS) formation induced by high glucose-mediated activation of the mitochondrial electron-transport chain is an early event in the development of diabetic complications. A variety of growth factors and cytokines are then induced through complex signal transduction pathways involving protein kinase C, mitogen-activated protein kinases, and the transcription factor NF-kappaB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines. Particularly, TGF-beta is important in the development of renal hypertrophy and accumulation of extracellular matrix components. Activation of the renin-angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes many of the pathophysiological changes associated with diabetic nephropathy. In fact, it has been shown that angiotensin II is involved in almost every pathophysiological process implicated in the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, interstitial inflammation). Consequently, blocking these deleterious effects of ANG II is an essential part of every therapeutic regiment to prevent and treat diabetic nephropathy. Recent evidence suggests that regression of diabetic nephropathy could be achieved under certain circumstances.
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PMID:New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. 1560 19

Recent studies demonstrate low serum levels of 25-hydroxyvitamin D in patients with congestive heart failure (CHF). Although this may in part reflect reduced capacity for outdoor exercise, the possibility that poor vitamin D status increases risk for left ventricular hypertrophy (LVH), and its common sequel CHF, merits consideration. In cardiomyocytes, hormones which activate protein kinase C (PKC) -- including norepinephrine, angiotensin II, and endostatin, implicated in the pathogenesis of LVH -- induce a hypertrophic response analogous to that seen in LVH. Transgenic mice overexpressing PKC-beta2 or its upstream activator Galphaq in cardiac myofibers develop a syndrome similar to LVH. Parathyroid hormone (PTH) also activates Galphaq and PKC in cardiomyocytes, and provokes the expected hypertrophic response. Both primary and secondary hyperparathyroidism are associated with high risk for LVH. Moreover, in uncomplicated essential hypertension, left ventricular mass index has been shown to correlate very tightly with serum PTH levels, independent of blood pressure. This latter finding suggests that variations of PTH within the normal range can influence induction of LVH in at-risk subjects. If so, nutritional and lifestyle measures which modulate PTH secretion may have an impact on LVH risk. PTH secretion should be down-regulated by good vitamin D status -- achieved through supplementation or regular uv exposure -- and by vegan diets moderately low in bioavailable phosphate. Although high calcium intakes can likewise suppress PTH, they also boost renin secretion, which could have a countervailing effect on risk for LVH. Whether these nutritional measures do indeed influence LVH risk could be examined in prospective studies targeting patients at high risk, such as hypertensives.
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PMID:Nutritional modulation of parathyroid hormone secretion may influence risk for left ventricular hypertrophy. 1578 May 3

Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgA nephropathy (IgAN). Previous data showed an altered glomerular expression of angiotensin II type 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. In this study, the expression and regulation of Ang II receptors were examined in human proximal tubular epithelial cells (PTEC) in IgAN. Tubular expression of AT1R and Ang II type 2 receptor (AT2R) was increased in IgAN. In vitro culture experiment showed that the upregulation of Ang II receptors was not due to the direct effect of IgA but the indirect effect after IgA deposition on human mesangial cell. When PTEC were cultured with conditioned culture medium from human mesangial cells activated with IgA, Ang II production was upregulated, leading to inflammation and apoptosis via the AT1R and AT2R, respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the conditioned medium. The initial interaction between Ang II and AT1R activated both protein kinase C and mitogen-activated protein kinase pathways, leading to inflammatory responses. This early AT1R-dependent event was followed by upregulation of AT2R expression and continued Ang II release. The interaction between Ang II and AT2R subsequently led to expression of cleaved poly[ADP-ribose] polymerase through downregulation of the mitogen-activated protein kinase pathway. The data suggest that appropriate control of Ang II receptor activities in PTEC may ameliorate tubulointerstitial injury in IgAN.
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PMID:Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy. 1593 94

The renin-angiotensin system (RAS) is linked with the vascular motion and the secretion of aldosterone. The purpose of the present study was to elucidate whether angiotensin II (Ang II) induces monocytes (Mo) to express tissue factor (TF) and if Ang II subtype 1 receptor (AT1R) antagonists inhibit the effect of Ang II. The roles of different intracellular signal transduction pathways and IkappaB/NF-kappaB in Ang II-induced TF expression of Mo were also studied to explore the mechanisms involved. Mo were isolated from heparinized human blood by a two-step gradient centrifugation, cultured in RPMI-1640 and exposed to Ang II and other test reagents. Mo TF activity and TF antigen were determined with a one-stage clotting method and ELISA, respectively, after the culture. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the TF mRNA levels in Mo. The level of IkappaBalpha in Mo was detected by Western blot analysis. Electrophoresis mobility shift assay (EMSA) was performed to evaluate the binding activity of NF-kappaB in Mo. The experiment results are as follows: (1) Ang II (10(-10)-10(-7) M) induced Mo to express TF activity but had no marked effect on other mononuclear cells. Ang II 10(-10)-10(-7) M) also caused increased TF mRNA expression and TF antigen from Mo in a dose-dependent manner. The TF antigen of Mo was elevated at 4 h after Mo was exposed to Ang II (10(-7) M) in culture, reached the peak at 6 h, and then declined from 12 h. The changes of TF activity were positively correlated with those of TF antigen. TF mRNA expression was elevated at 1 h, peaked at 3 h, and declined after 8 h. (2) Losartan (10(-6)-10(-5) M) significantly inhibited the stimulative effects of Ang II on TF activity, TF antigen and TF mRNA in Mo in a dose-dependent manner. (3) The protein kinase C (PKC) inhibitor, staurosporine, and the protein tyrosine kinase (PTK) inhibitor, genistein, both lowered TF levels in Mo, but the inhibitory effect of staurosporine was stronger than that of genistein. The effect of mitogen-activated protein kinase (MAPK) inhibitor, U0126, on monocytic TF expression was not significant. (4) Western blot analysis revealed that after Ang II (10(-7) M)exposure, levels of IkappaBalpha began to decrease at 15 min, reached a nadir at 60 min (P<.01), and recovered at 180 min. (5) EMSA showed that NF-kappaB binding activity started to increase at 15 min, reached a peak at 60 min, and returned to baseline at 180 min. The present data suggest that Ang II can directly induce TF expression in human Mo and this effect is mediated by AT1R. PKC may play the most important role in Ang II-induced TF expression among the three signal pathways detected. In addition, activation of NF-kappaB is also involved in the TF expression of Mo induced by Ang II.
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PMID:Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes. 1595 27

Although advanced glycation end products (AGEs) have been postulated to contribute to diabetic nephropathy in their own right, advanced glycation is clearly only one pathway by which renal injury may be induced in diabetes. The interaction between metabolic and hemodynamic factors amplifies the deleterious effects of the diabetic milieu, thereby reducing the threshold for microvascular injury via common mechanisms. This includes interactions between AGE-mediated pathways and the renin angiotensin system, oxidative stress, protein kinase C, and growth factors, which play a significant role in the development and progression of diabetic renal disease. As it is likely that the future of preventive therapy will not involve a single "cure-all" agent, it seems that a highly relevant question in diabetic nephropathy should be, which pathogenic pathways are already addressed by currently available therapies? Combination therapies that target multiple pathways may ultimately be more successful than those that modify a single pathway. Therefore, research into synergistic interactions among the various pathogenic pathways leading to diabetic complications is critical in order to develop interventions that confer optimal end-organ protection.
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PMID:Can advanced glycation end product inhibitors modulate more than one pathway to enhance renoprotection in diabetes? 1603 2

Staurosporine (STS) is a very potent broad-range kinase inhibitor, and its antiproliferative properties made it a lead compound for protein kinase C (PKC) inhibitors with therapeutic potential. Because STS also causes hypotension, we investigated in this study whether it directly interferes with the terminal steps of aldosterone biosynthesis; these are catalysed by a mitochondrial steroid hydroxylase system consisting of adrenodoxin reductase, adrenodoxin, and the cytochrome P450 enzyme hCYP11B2 (aldosterone synthase). Here we demonstrate that nanomolar concentrations of STS significantly reduced aldosterone synthase activity in transiently transfected COS-1 cells and in stably transfected V79MZh11B2 cells (IC50 = 11 nM). However, STS did not inhibit bovine aldosterone synthase in a reconstituted steroid hydroxylation assay. In transiently transfected COS-1 cells, the protein level of adrenodoxin (but not that of adrenodoxin reductase or of hCYP11B2) was significantly reduced after treatment with 2 nM STS. Finally, we show that STS treatment (1 microg/day) of mice reduced their aldosterone/renin ratio by almost 50% (p = 0.015). To the best of our knowledge, this is the first report of a direct in vivo effect of STS on the renin-angiotensin-aldosterone system. We conclude (i) that the hypotensive effect of staurosporine is at least partly due to inhibition of aldosterone biosynthesis via adrenodoxin depletion, and (ii) that aldosterone biosynthesis can be regulated in vivo at the level of adrenodoxin availability.
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PMID:Inhibition of aldosterone biosynthesis by staurosporine. 1620 87


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