Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metalion vanadate has insulin-like effects and has been advocated for use in humans as a therapeutic modality for diabetes mellitus. However, since vanadate is a tyrosine phosphatase inhibitor, it may result in undesirable activation of target cells. We studied the effect of vanadate on human mesangial cells, an important target in diabetic nephropathy. Vanadate stimulated DNA synthesis and PDGF B chain gene expression. Vanadate also inhibited total tyrosine phosphatase activity and stimulated tyrosine phosphorylation of a set of cellular proteins. Two chemically and mechanistically dissimilar tyrosine kinase inhibitors, genistein and herbimycin A, blocked DNA synthesis induced by vanadate. Vanadate also stimulated phospholipase C and protein kinase C. Downregulation of protein kinase C abolished vanadate-induced DNA synthesis. Thus, vanadate-induced mitogenesis is dependent on tyrosine kinases and protein kinase C activation. The most likely mechanism for the effect of vanadate on these diverse processes involves the inhibition of cellular phosphotyrosine phosphatases. These studies demonstrating that vanadate activates mesangial cells may have major implications for the therapeutic potential of vanadate administration in diabetes. Although vanadate exerts beneficial insulin-like effects and potentiates the effect of insulin in sensitive tissue, it may result in undesirable activation of other target cells, such as mesangial cells.
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PMID:Activation of mesangial cells by the phosphatase inhibitor vanadate. Potential implications for diabetic nephropathy. 788 73

Angiotensin-II (ANG-II) is a potent endocrine and paracrine hormone that functions in humans through two distinct G-protein-coupled transmembrane receptor subtypes (AT-1 and AT-2). ANG-II is found in nearly all tissues of the body including the brain, heart, kidneys, gonads, and gastrointestinal tract. Just as it is found in nearly every organ system of the body, so is it involved in an array of physiologic processes from fetal development to blood pressure control. ANG-II regulates blood pressure by controlling sodium reabsorption in the proximal tubule, altering the glomerular filtration rate and renal blood flow, and by modifying the production and release of aldosterone in the adrenal gland. Additionally, ANG-II is involved in several pathologic processes including the development of hypertension, cardiomyopathy, atherosclerosis, and diabetic nephropathy. It is able to exert influences in these widely varying processes by working together with multiple different second messenger systems including the MAP kinase pathway, nitric oxide production, and phospholipase C and D, and several arachidonic acid metabolites. This paper is a review of the current knowledge of ANG-II and its receptors in health and disease.
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PMID:Action of angiotensin receptor subtypes on the renal tubules and vasculature: implications for volume homeostasis and atherosclerosis. 993 Mar 75

Alteration of [Ca2+]i by hyperglycemia is implicated in the pathogenesis of diabetic nephropathy. However, the effect of high glucose on Ca2+ regulation in proximal tubule cells is not known. Thus, we examined the mechanisms by which high glucose regulates Ca2+ uptake in primary cultured rabbit renal proximal tubule cells. Glucose increased the Ca2+ uptake in a time- and dose-dependent manner. A stimulatory effect of high glucose on Ca2+ uptake is predominantly observed using 25 mM glucose (high glucose) after 1 h, while 25 mM glucose did not affect cell viability and lactate dehydrogenase release. However, 25 mM mannitol and L-glucose did not affect Ca2+ uptake as compared with controls. Nifedipine and methoxyverapamil (L-type Ca2+ channel blockers) blocked high-glucose-induced stimulation of Ca2+ uptake. High-glucose-induced stimulation of Ca2+ uptake was blocked by pertussis toxin, SQ-22536 (adenylate cyclase inhibitor), myristoylated amide 14-22 (protein kinase A inhibitor), neomycin and U-73122 (phospholipase C inhibitors), and staurosporine and bisindolylmaleimide I (protein kinase C inhibitors). In addition, KN-62 (a Ca2+/calmodulin-dependent protein kinase II inhibitor) and W-7 (a Ca2+/calmodulin antagonist) blocked high-glucose-induced stimulation of Ca2+ uptake. In conclusion, high glucose stimulates the Ca2+ uptake through L-type Ca2+ channels via G-protein-coupled adenylate cyclase/cAMP and phospholipase C/protein kinase C pathways.
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PMID:High glucose stimulates Ca2+ uptake via cAMP and PLC/PKC pathways in primary cultured renal proximal tubule cells. 1117 1

The studies concerning the structure and variations of the human adrenomedullin (AM) gene are reviewed, and their relations to the gene function and genetic predisposition to cardiovascular diseases are discussed. The genomic human AM gene is composed of four exons, and the whole nucleotide sequence corresponding to mature AM resides in the fourth exon. In chromosomal sublocalization, the AM gene is located in the distal portion of the short arm of chromosome 11 (11p15.1-3). Analysis of the promoter region of the AM gene has revealed that two transcription factors, nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2), participate in the regulation of AM gene expression. It is surmised that NF-IL6 mediates inflammatory stimuli and AP-2 mediates signals of phospholipase C and protein kinase C activation. In addition to these factors, hypoxia induces AM gene expression via the hypoxia inducible factor-1 (HIF-1) binding site. The 3'-end of the AM gene is flanked by a microsatellite marker of cytosine adenine (CA) repeats. In Japanese, there are four types of alleles with different CA-repeat numbers: 11, 13, 14 and 19. It is suggested that existence of the 19-repeat allele is associated with genetic predispositions to develop essential hypertension and diabetic nephropathy.
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PMID:Variations of human adrenomedullin gene and its relation to cardiovascular diseases. 1263 Aug 23

In diabetic patients, the elevation of plasma prorenin levels or arterial pressure is correlated with the severity of diabetic nephropathy. This study was designed to assess the effects of transmural pressure on prorenin regulation in juxtaglomerular (JG) cells from diabetes rats. The JG cells, harvested from rats intraperitoneally injected with streptozotocin 7 (early-diabetic) or 28 (late-diabetic) days previously, were exposed to atmospheric pressure (AP) and AP+40 mmHg for 12 h, and the renin secretion rate (RSR), prorenin secretion rate (PRSR), active renin content (ARC), prorenin content (PRC), and total renin content (TRC) were determined. Exposure of control JG cells to AP+40-mmHg significantly decreased RSR, PRSR, and ARC and significantly increased PRC without affecting TRC, suggesting the occurrence of pressure-mediated inhibition of prorenin processing and secretion. Exposure of early-diabetic and late-diabetic cells to AP+40-mmHg significantly decreased ARC and significantly increased PRC without affecting RSR, PRSR, or TRC. The changes in ARC and PRC were similar in the control and early-diabetic cells, but greater changes were observed in late-diabetic cells. However, when streptozotocin-treated rats were continuously treated with insulin (9 U/kg/day), the transmural pressure control of prorenin in JG cells was similar to that observed in the JG cells from control rats. In late-diabetic cells, treatment with a phospholipase C inhibitor did not alter the pressure control of ARC or PRC; however, treatment with a phospholipase D inhibitor did inhibit the changes in ARC and PRC with transmural pressure. Thus, pressure-mediated inhibition of prorenin secretion from JG cells has already been impaired in early diabetes. Pressure-induced inhibition of prorenin processing in JG cells via phospholipase D-dependent pathways is enhanced in late diabetes.
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PMID:Transmural pressure control of prorenin processing and secretion in diabetic rat juxtaglomerular cells. 1286 7

The globally increasing number of patients with end-stage renal disease urges the identification of molecular pathways involved in renal pathophysiology, to serve as targets for intervention. Moreover, the identification of genetic risk factors or protective genes can aid tailored therapy. Tools that can be used to identify genes involved in renal disease include gene expression arrays, linkage analysis and association studies. Arrays are a powerful and widely used approach to the analysis of gene transcription and protein expression, whereas linkage analysis and association studies link disease susceptibility to particular genetic regions. Animal models are available to pinpoint the disease-associated genes. Candidate genes so far identified in renal disease include those encoding the podocyte proteins nephrin and podocin, the transcription factor WT1, the calcium channel TRPC6 and the enzyme phospholipase C-epsilon-1 (in congenital nephrotic syndrome and focal segmental glomerulosclerosis), and carnosinase (in diabetic nephropathy). In addition, linkage studies have identified chromosomal regions implicated in systemic lupus erythematosus, diabetic nephropathy and familial IgA nephropathy. Future studies will elucidate the emerging role of epigenetic regulation of gene expression in renal disease.
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PMID:Primer: strategies for identifying genes involved in renal disease. 1836 21

Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca(2+) increase due to depletion of luminal ER Ca(2+). Palmitate-induced ER Ca(2+) depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca(2+) pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca(2+) depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca(2+) loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca(2+) depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca(2+) depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury.
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PMID:Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. 2658 19