Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of the mitogen-activated protein kinase cascade is one of the major signalling pathways by which growth factors transmit their mitogenic messages from the cell membrane to the nucleus. Two major breakthroughs reported in the past months are the cross-communication between the mitogen-activated protein kinase cascade and the cAMP-protein kinase A signal pathway, and the role of alpha- and beta gamma-complexes of heterotrimeric G proteins in activating the mitogen-activated protein kinase pathway. These signalling strategies have now also been demonstrated in renal mesangial cells. Another important step has been the identification of a candidate gene for polycystic kidney disease. Knowledge of the molecular mechanisms of action of growth factors in the kidney will promote greatly our understanding of the aetiology of renal disease.
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PMID:Proliferative mechanisms in kidney cells. 774 66

Impaired heparan sulphate biosynthesis through diabetes-induced inhibition of glucosaminyl N-deacetylase may have a central role in the development of diabetic nephropathy, and genetic differences in the vulnerability of the N-deacetylase could influence the risk of developing nephropathy. We studied N-deacetylase activity in fibroblast cultures from Type 1 (insulin-dependent) diabetic patients with (n = 14) or without (n = 13) diabetic nephropathy, together with non-diabetic control subjects (n = 7). No difference in N-deacetylase activity was found (p = 0.13), and no inhibition of N-deacetylase was found in cultures grown at 25 mmol/l glucose. N-deacetylase activity was inversely correlated to growth rate (r = -0.59, p = 0.0008), and in patients with nephropathy a negative correlation between HbA1C and fibroblast N-deacetylase activity (r = -0.72, p = 0.012) was found. Cell-cycle analysis revealed an increased fraction of S-phase cells in patients with nephropathy (28%(21-52%)) compared to healthy control subjects (17% (9-24%)), p = 0.0008, but not between patients with and without nephropathy (latter group 26%(11-43%)), p = 0.43. Forskolin, an activator of protein kinase A, specifically decreased N-deacetylase activity, whereas activation of protein kinase C produced a combined reduction in N-deacetylase activity and total protein synthesis. In conclusion, no constitutive defects in N-deacetylase activity were found in fibroblasts from these patients. Further studies should consider possible associations between fibroblast characteristics and pre-biopsy environmental parameters related to cellular memory phenomena. Finally, activation of protein kinase A provides a potential general pathway for regulating N-deacetylase activity.
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PMID:Glucosaminyl N-deacetylase in cultured fibroblasts; comparison of patients with and without diabetic nephropathy, and identification of a possible mechanism for diabetes-induced N-deacetylase inhibition. 833 76

Hypertension is a multifactorial disorder that results in an increased risk of cardiovascular and end-stage renal disease. Liddle's disease represents a specific hypertensive disease and expresses itself in the human population as an autosomal dominant trait. Recent experimental evidence indicates that patients with Liddle's disease have constitutively active amiloride-sensitive Na+ channels and that these channels are phenotypically expressed in lymphocytes obtained from normal and affected members of the original Liddle's kindred. Linkage analysis indicates that this disease results from a deletion of the carboxy-terminal region of the beta-subunit of a recently cloned epithelial Na+ channel (ENaC). We report the successful immunopurification and reconstitution of both normal and constitutively active lymphocyte Na+ channels into planar lipid bilayers. These channels display all of the characteristics typical of renal Na+ channels, including sensitivity to protein kinase A phosphorylation. We demonstrate that gating of normal Na+ channels is removed by cytoplasmic trypsin digestion and that the constitutively active Liddle's Na+ channels are blocked by a beta- or gamma-ENaC carboxy-terminal peptide in a GTP-dependent fashion.
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PMID:Peptide block of constitutively activated Na+ channels in Liddle's disease. 877 47

To understand better the function of endothelin-1 (ET-1) in renal physiology, we examined vascular and glomerular expression of ET-1 in normal human kidney and in lupus nephritis. Immunohistochemical analysis revealed that renal endothelium of glomeruli, arteries, veins, and capillaries expressed ET-1. Endothelial cells were the principal source of glomerular ET-1; positive immunostaining was detected only rarely in mesangial cells and vascular smooth muscle cells from normal kidney. However, mesangial staining for ET-1 was elevated in patients with lupus nephritis, suggesting that under certain conditions mesangial cells elaborate ET-1. Indeed cultured human mesangial cells from normal subjects secreted ET-1 peptide. ET-1 secretion was augmented by the protein kinase C activator phorbol ester and by transforming growth factor-beta1 (TGF-beta1), a cytokine implicated in the development of glomerulosclerosis. Transient transfection of cultured mesangial cells with a preproET-1 reporter construct showed that the preproET-1 promoter is transcriptionally active in mesangial cells and is stimulated by TGF-beta1, phorbol ester, or ectopic expression of protein kinase beta1. Cultured human mesangial cells have both ETA and ETB receptors that contribute to ET-1-stimulated mitogenesis. Taken together, these results demonstrate that ET-1 is expressed at sites where paracrine or autocrine signaling by ET-1 might control renal vasoconstriction, glomerular filtration rate, and remodeling of the glomerulus in renal disease.
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PMID:Vascular and glomerular expression of endothelin-1 in normal human kidney. 968 99

Diabetes mellitus is a complex disease characterised by chronic hyperglycaemia responsible for complications affecting the kidneys, eyes, peripheral nerves and micro- and macrovascular systems. Von Willebrand factor (vWf), a multimeric glycoprotein mainly synthesised by endothelial cells, is involved in platelet adhesion and aggregation and acts as the carrier of coagulation factor VIII in plasma. Increased levels of vWf, reflecting activation of or damage to endothelial cells, have been described in association with atherosclerosis and diabetes. vWf appears to be a predictive marker of diabetic nephropathy and neuropathy, although not of retinopathy, which suggests that endothelial dysfunction precedes the onset of diabetic microangiopathy. This dysfunction could be especially involved in the pathogenesis of renal abnormalities of diabetes. vWf is not a predictive marker of macroangiopathy when diabetes is associated with atherosclerotic risk factors. In the presence of chronic diabetic complications, vWf levels are not associated with any grade of retinopathy but increase with the severity of nephropathy and would appear to be a risk factor for macrovascular mortality in these patients. The endothelial dysfunction of diabetes can generate atherosclerotic lesions responsible for damage to the arterial wall, atheroma and formation of platelet microaggregates. Concomitant with high vWf levels, other possible mechanisms of endothelial damage include reduced synthesis or release of nitric oxide, hyperglycaemic pseudohypoxia and protein kinase-C activation, increased synthesis of proteins bearing advanced glycosylation end-products or transforming growth factor-beta (TGF-beta) activation of coagulation and inhibition of fibrinolysis. At present, it is not known whether high vWf levels are inherent to the physiopathology of diabetes, nor whether diabetes induces endothelial dysfunction through other pathways. However, since angiopathy resulting from endothelial dysfunction is the main cause of morbidity and mortality in diabetic patients, appropriate therapy is necessary to reduce these complications. Glycaemic control seems to be insufficient to normalise plasma vWf, whereas a decrease can be obtained by ingestion of diets rich in oleic acid or by treatment with statins. Inhibition of the binding of vWf to the GPlba receptor by synthetic peptides, aurin tricarboxylic acid or monoclonal antibodies has been proposed to prevent the thrombosis induced by high levels of plasma vWf. Thus, vWf probably represents an interesting target for the inhibition of thrombosis in diabetes.
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PMID:Von Willebrand factor in diabetic angiopathy. 980 43

MRL-lpr/lpr mice have a Fas receptor mutation that leads to abnormalities of apoptosis, lymphoproliferation, and a lupus-like autoimmune disease associated with the production of autoantibodies. Other than Fas pathway defects, little is known about molecular abnormalities that predispose to autoimmunity. Protein kinase CK2 (also termed casein kinase II), a serine-threonine protein kinase whose targets include many critical regulators of cellular growth, is highly expressed in a lymphoproliferative disease of cattle and in many human cancers. Overexpression of the CK2alpha catalytic subunit in lymphocytes of transgenic mice leads to T cell lymphoma. We hypothesized that CK2 dysregulation and Fas mutation might cooperatively augment lymphocyte proliferation and transformation. We find that in MRL-lpr/lpr mice bearing the CK2alpha transgene, the lymphoproliferative process is dramatically exacerbated, as these mice develop massive splenomegaly and lymphadenopathy by 12 wk of age in association with increased autoantibody production and accelerated renal disease. The lymphoid organs are filled with the unusual B220+CD4-CD8- T cells typically seen in MRL-lpr/lpr mice, not the B220-CD4+CD8+ or B220-CD4-CD8+ T cells typically seen in CK2a transgenic lymphomas. The T cells do not fulfill the criteria for transformation, as they are polyclonal and not transplantable or immortal in cell culture. Thus, although the lpr lymphoproliferative and autoimmune syndrome is potentiated by the presence of the CK2a transgene, this combination of apoptotic and proliferative abnormalities appears to be insufficient to transform lymphoid cells.
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PMID:Acceleration of lpr lymphoproliferative and autoimmune disease by transgenic protein kinase CK2 alpha. 982 Apr 86

Several recent studies have provided clear evidence that angiotensin-converting enzyme (ACE)-inhibitors slow the progression of renal disease. These effects are mainly independent from a comitant reduction in systemic blood pressure. Thus, angiotensin II (Ang II) exerts other effects on the kidney which are involved in the loss of renal function. Ang II induces proliferation of cultured mesangial and glomerular endothelial cells. Our group was the first to demonstrate that Ang II stimulates hypertrophy of cultured proximal tubular cells. Ang II stimulates bioactivation and expression of transforming growth factor-beta (TGF-beta) in tubular MCT cells. This Ang II-mediated expression of TGF-beta is due to an increase in transcriptional activity. A neutralizing anti-TGF-beta antibody attenuates the Ang II-induced increase in protein synthesis in MCT cells suggesting that the hypertrophy is mediated by synthesis and activation of endogenous TGF-beta. Proximal tubular cells undergoing Ang II-mediated hypertrophy are arrested in the G1-phase of the cell cycle and express typical G1-phase-associated genes. Induction of such G1-phase-associated early growth response genes have been also described in vivo after infusion of Ang II into the renal artery. This G1-phase arrest depends on the induction of the cyclin-dependent kinase (CdK) inhibitor p27Kip1. p27Kip1 expression is stimulated after incubation of LLC-PK1 cells with Ang II or TGF-beta and binds to cyclin D1-CdK4 complexes, inhibits their kinase activity, and hampers G1-phase exit. Ang II stimulates transcription of collagen type IV in MCT cells. In addition to the classical a1 (IV) chain, a3 (IV) collagen, which has normally a restricted localization in the kidney, is also induced. This stimulation is mediated by endogenous synthesis and autocrine action of TGF-beta because a neutralizing anti-TGF-beta antibody as well as TGF-beta antisense oligonucleotides attenuate Ang II-induced collagen type IV transcription and synthesis. In addition, Ang II exerts immunomodulatory effects on the kidney through the induction of chemokines such as MCP-1 and RANTES. In conclusion, Ang II has emerged as a multifunctional acting as a growth factor and a profibrogenic cytokine, and even having inflammatory properties.
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PMID:Angiotensin II is involved in the progression of renal disease: importance of non-hemodynamic mechanisms. 985 83

The response to glomerular and tubulointerstitial cell injury in most forms of renal disease includes changes in cell number (proliferation and apoptosis) and cell size (hypertrophy). These events typically precede and may be responsible for the accumulation of extracellular matrix proteins that leads to a decrease in renal function. There is increasing evidence showing that positive (cyclins and cyclin-dependent kinases) and negative (cyclin-dependent kinase inhibitors) cell cycle regulatory proteins have a critical role in regulating these fundamental cellular responses to immune and nonimmune forms of injury. Data now show that altering specific cell cycle proteins affects renal cell proliferation and improves renal function. Equally exciting is the expanding body of literature showing novel biological roles for cell cycle proteins in the regulation of cell hypertrophy and apoptosis. With increasing understanding of the role for cell cycle regulatory proteins in renal disease comes the hope for potential therapeutic interventions.
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PMID:Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. 1075 Dec 12

Secondary hyperparathyroidism (SH) and hyperplasia of the parathyroid glands (PTG) are universal complications in patients with CRF. In early renal failure, reduction in serum calcitriol and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, a reduction in parathyroid expression of vitamin D receptor and calcium receptor renders the PTG more resistant to both calcitriol and calcium. High dietary phosphorus (P), independent of calcium and calcitriol, further enhances uremia-induced PTG hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms. Once SH develops, dietary P restriction can return the high serum PTH levels toward normal, however, parathyroid hyperplasia persists. Studies in our laboratory identified 2 of the mechanisms involved in the opposing effects of high and low dietary P content on PTG growth. Whereas high dietary P increases parathyroid expression of transforming growth factor alpha (TGFalpha), a growth promoter, P restriction induces the cyclin-dependent kinase inhibitor p21, an inducer of growth arrest. Both effects of P are specific for the PTG. No increase in either protein was observed in liver or intestine. TGFalpha induction of hyperplasia involves binding to the epidermal growth factor receptor and activation of mitogen activated protein (MAP) kinases cascades. p21 blocks progression through the cycle and cell division by inactivating cyclin/cyclin-dependent kinase complexes. Preventing hyperphosphatemia and elevated Ca x P product in renal failure not only ameliorates the progression of SH and bone disease but also the morbidity and mortality resulting from vascular calcification.
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PMID:Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. 1115 62

Nitric oxide (NO) levels are increased after exposure of cultured proximal tubule cells (PTC) to non-haem iron, potentially contributing to PTC injury in disease states associated with increased iron exposure, including proteinuric renal disease. The mechanisms underlying this observed increase were investigated. After 3 h exposure to 400 microM nitrilotriacetate (NTA)-Fe, inducible nitric oxide synthase (iNOS) mRNA expression was significantly increased, with a corresponding increase in iNOS protein after 12 h. The nuclear binding activity of NFkappaB with 400 microM NTA-Fe was increased, and pyrrolidine dithiocarbamate (PDTC), an antioxidant inhibitor of NFkappaB, prevented both activation of NFkappaB and NO production in response to NTA-Fe. Inhibition of protein tyrosine kinase reduced iNOS mRNA, iNOS protein levels and NO production in response to NTA-Fe. The effect of tyrosine kinase inhibition on NFkappaB activation was variable, with herbimycin but not genistein having an inhibitory effect. Activation of either protein kinase A or C increased iNOS mRNA and protein levels, and NO production in response to NTA-Fe, whereas only the protein kinase C activator phorbol dibutyrate (PDBu) had a stimulatory effect on NFkappaB activation. The protein kinase A activator forskolin did not alter iron-induced activation of NFkappaB. These data suggest that the observed increase in NO production by PTC in response to iron is due to increased transcription of iNOS. The transcriptional regulation of this response is complex and involves NFkappaB, protein tyrosine kinase and the protein kinases A and C.
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PMID:Molecular mechanisms by which iron induces nitric oxide synthesis in cultured proximal tubule cells. 1134 Mar 4


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