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)

Leukocyte adhesion to kidney cells is an early event in renal inflammation, such as glomerulonephritis. We developed an experimental model of monocyte adhesion to cultured human mesangial cells. U-937 myelomonocytic leukaemia cells, similar to peripheral blood human monocytes, irreversibly bound to mesangial cell monolayers upon 30-180 min coincubations (to a max. of 13,600 +/- 1100/cm2 monolayer), as assessed by cell counting, U-937 labelling with 3H-thymidine, and colorimetry of nuclear staining with crystal violet. Adhesion was enhanced in mesangial cells proliferating in response to 17% fetal bovine serum, indicating expression of a proinflammatory phenotype. E. coli lipopolysaccharide (LPS), tumour necrosis factor-alpha (TNF-alpha) and protein kinase C activation with phorbol myristate acetate (PMA) potentiated monocyte binding during either coincubation or 24-h pretreatment (0.1 microM PMA, +200 +/- 21%). Binding was also promoted by pretreatment with vasoconstrictors, such as the thromboxane A2 mimetic, U-46619 (10 nM-1 microM, max. +35 +/- 3%), or 1 microM angiotensin II (+64 +/- 4%). To elucidate the mechanisms of monocyte adhesion, we analysed the adhesion molecules expressed by human mesangial cells, employing reverse transcription/polymerase chain reaction to detect ICAM-1, VCAM-1 and E-selectin gene expression. Proliferating cells express VCAM-1 and ICAM-1, confirmed by immunocytochemical staining and 79 +/- 3% inhibition of stimulated adhesion by pretreatment of mesangial cells with an anti-ICAM-1 monoclonal Ab. E-selectin transcription was not detectable.(ABSTRACT TRUNCATED AT 250 WORDS)
Nephrol Dial Transplant 1995
PMID:Regulation of U-937 monocyte adhesion to cultured human mesangial cells by cytokines and vasoactive agents. 754 54

The effect of histamine on the phosphoinositide turnover and intracellular free calcium activity [Ca2+]i was examined in human glomerular epithelial cells in culture. Addition of histamine to glomerular epithelial cells resulted in formation of inositol phosphates in a time- and dose-dependent manner. A transient maximum of inositol trisphosphate (InsP3) was observed within 10 s. Stimulation of protein kinase C by short-term pretreatment (15 min) of glomerular epithelial cells with phorbol 12-myristate 13-acetate caused a dose-dependent inhibition of the histamine-induced inositol phosphate accumulation. The baseline of [Ca2+]i in the cells was 115 +/- 2.7 nmol/l (n = 103). Histamine (ED50: approx. 2 x 10(-7) mol/l) caused a rapid and transient increase in [Ca2+]i as detected by fura-2 microfluorimetry studies. In a calcium-free extracellular solution the rapid increase of [Ca2+]i was still present. The H1 receptor antagonist mepyramine (IC50: approx. 8 x 10(-9) mol/l) inhibited the histamine (10(-6) mol/l) response on [Ca2+]i. Cimetidine, a potent H2 receptor antagonist, showed no effect. This data indicates that H1 receptor activation causes hydrolysis of phosphatidylinositol 4, 5-bisphosphate by phospholipase C activation, and consecutive mobilization of intracellular calcium. Since histamine is a mediator of inflammation, antigen response and cellular injury, these findings could be of importance for the understanding of glomerular epithelial cell pathology.
Nephrol Dial Transplant 1994
PMID:Effects of histamine on inositol phosphates and intracellular Ca2+ in human glomerular epithelial cells. 797 Jan 17

Fibrin formation within the glomeruli occurs in various forms of human and experimental glomerulonephritis and it may play an important role in progressive glomerular injury. Transforming growth factor-beta (TGF-beta) has been shown to participate in the glomerular accumulation of extracellular matrix in glomerulonephritis. We investigated whether thrombin, an important coagulation factor, could modulate the production of TGF-beta by cultured human mesangial cells (HMC). TGF-beta levels in the culture supernatants were measured by ELISA using a specific antibody. The TGF-beta concentration was significantly increased by incubation of HMC with thrombin in a time-dependent manner. The stimulating effect of thrombin on TGF-beta was inhibited by addition of hirudin (a natural thrombin inhibitor) and argatroban (a synthetic thrombin inhibitor). In addition DFP-inactivated thrombin, which has no enzymatic activity, did not stimulate TGF-beta production. A protein kinase C inhibitor (H7) and a tyrosine kinase inhibitor (herbimycin A) also inhibited thrombin induced TGF-beta production. These findings suggested that thrombin may modulate the synthesis of TGF-beta via protein kinase C- and tyrosine kinase-dependent mechanisms in cultured HMC. Thus thrombin may participate in the accumulation of extracellular matrix in glomeruli through the augmentation of TGF-beta production.
Nephrol Dial Transplant 1997 Mar
PMID:Thrombin stimulates production of transforming growth factor-beta by cultured human mesangial cells. 907 21

Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway. The major source of DAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates. Among the various PKC isoforms, the beta-isoform has been shown to be persistently activated in diabetic animals. Multiple lines of evidence have shown that many vascular alterations in diabetes--such as a decrease in the activity of Na+-K+-adenosine triphosphatase (Na+-K+-ATPase), and increases in extracellular matrix, cytokines, permeability, contractility, and cell proliferation--are caused by activation of PKC. Inhibition of PKC by two different kinds of PKC inhibitors, LY333531, a selective PKC-beta-isoform inhibitor, and d-alpha-tocopherol, were able to prevent or reverse the various vascular dysfunctions in diabetic rats. These results have also provided in vivo evidence that DAG-PKC activation could be responsible for the hyperglycemia-induced vascular dysfunctions in diabetes. Clinical studies are now being performed to clarify the pathogenic roles of the DAG-PKC pathway in developing vascular complications in diabetic patients.
Perit Dial Int 1999
PMID:The role of protein kinase C activation in the pathogenesis of diabetic vascular complications. 1040 23

Encapsulating peritoneal sclerosis (EPS) remains one of the major causes of dropout in continuous ambulatory peritoneal dialysis by reducing ultrafiltration capacity. To demonstrate whether ascites from patients with EPS (EPS ascites) has fibroblast proliferation activity, we used NIH/3T3 fibroblasts to examine the effects of EPS ascites on fibroblast proliferation activity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Encapsulating peritoneal sclerosis ascites dose-dependently augmented NIH/3T3 fibroblast proliferation. The protein kinase C inhibitors and the tyrosine kinase inhibitors partially inhibited the stimulatory effects of EPS ascites on fibroblast proliferation activity. In EPS ascites, levels of interleukin (IL)-1beta, IL-6, IL-8, transforming growth factor (TGF)-beta1, hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF)-AB were elevated. The treatment with IL-1beta, HGF, TGF-beta1, and PDGF-AB alone or in combination at similar concentrations to those in EPS ascites exhibited small but significant fibroblast proliferation activities. We conclude that EPS ascites stimulate NIH/3T3 fibroblast proliferation via protein kinase C and tyrosine kinase. The elevated cytokine and growth factors partly contribute to the EPS ascites-induced fibroblast proliferation.
Ther Apher Dial 2003 Oct
PMID:Ascites from patients with encapsulating peritoneal sclerosis augments NIH/3T3 fibroblast proliferation. 1470 5

Failure of the pancreatic beta cells to produce insulin or development of defective molecular signaling of insulin to the peripheral tissue cells (insulin resistance) induces persistent hyperglycemia and accumulation of fatty acids in the blood of patients with diabetes. Over time, those changes lead to microvascular and macrovascular damage in various target organs. In patients on peritoneal dialysis (PD), complications may accelerate with treatment using conventional glucose-containing solutions. Strategies for proper glycemic control in diabetic PD patients are therefore essential to prevent complications and to maintain a good quality of life. Dietary restrictions and weight control remain the foundation of the management approach for glycemic control. Further therapeutic actions include the stepwise addition of oral hypoglycemic agents and insulin, based on individual assessment of PD patients. Other strategies of immediate importance in reducing hyperglycemia are to use PD exchanges with new non glucose PD solutions (such as those with icodextrin or amino acids) in combination with fewer daily exchanges of low-glucose solutions. Combined, these approaches will sufficiently control hyperglycemia in diabetic PD patients. Research is in progress to develop therapeutic agents aimed at correcting various molecular defects of insulin signaling or at reducing protein kinase C activation induced by oxidative stresses in various tissue cells. Clinical experience with the use of such agents in diabetic PD patients is limited at present.
Adv Perit Dial 2004
PMID:Strategies for managing diabetic patients on peritoneal dialysis. 1538 26

A growing body of evidence indicates that the renal proximal tubular epithelial cell (PTEC) plays an important role in the pathogenesis of diabetic nephropathy (DN). Microalbuminuria that intensifies over time to overt proteinuria, a hallmark of DN, is already known to activate the PTEC to induce tubulointerstitial inflammation. In addition to proteins, a number of diabetic substrates including high glucose per se, advanced glycation end-products and their carbonyl intermediates, angiotensin II, and ultrafiltered growth factors activate a number of signaling pathways including nuclear factor kappa B, protein kinase C, extracellular signal-regulated kinase 1/2, p38, signal transducer and activator of transcription-1 and the generation of reactive oxygen species, to culminate in tubular cell hypertrophy and the accumulation in the interstitium of a repertoire of chemokines, cytokines, growth factors and adhesion molecules capable of orchestrating further inflammation and fibrosis. More recently, the kallikrein-kinin system (KKS) and toll-like receptors (TLRs) in PTECs have been implicated in this process. While in vitro data suggest that the KKS contributes to the progression of DN, there are conflicting in vivo results on its precise role, which may in part be strain-dependent. On the other hand, there are both in vitro and in vivo data to suggest a role for both TLR2 and TLR4 in DN. In this review, we offer a critical appraisal of the events linking the participation of the PTEC to the pathogenesis of DN, which we believe may be collectively termed diabetic tubulopathy.
Nephrol Dial Transplant 2012 Aug
PMID:The pathogenic role of the renal proximal tubular cell in diabetic nephropathy. 2273 10

The incidence of Type 2 diabetes is increasing rapidly worldwide, and understanding the mechanisms of its complications including diabetic nephropathy (DN) is important in the discovery of early biomarkers, understanding the causative mechanisms of its complications and identifying therapeutic targets. DN is characterized by glomerulosclerosis, tubulointerstitial fibrosis and tubular atrophy. The tubular component of the disease is important in progression of disease. In vitro models are a valuable alternative to animal studies and an effective way to explore mechanisms of human disease. Several proximal tubular cell lines have been used in studying mechanisms of DN. Key extracellular conditions that contribute to damage to the proximal tubule in DN include hyperglycaemia, proteinuria, and hypoxia and inflammation. According to current knowledge, these exert their effects through changes in transforming growth factor beta signalling, the renin-angiotensin system, dysregulation of pathways such as the polyol pathway, hexosamine pathway and protein kinase C pathway and through formation of advanced glycation end products. Studies in cell culture models have been instrumental in the delineation of these processes. However, all of the existing cell culture models have limitations including dedifferentiation. To bring research forward along with technological advances, such as major advances in 'omics' methodologies, a more suitable model is necessary. The RPTEC/TERT1 cell line is a promising alternative to previous proximal tubular epithelial cell lines due to features that resemble the cell type in vivo, such as its epithelial characteristics, maintenance of functional capabilities, glucose handling, expression of the primary cilium and transport activity including albumin. This cell line will facilitate identification of mechanisms of DN with potential to identify new therapeutic targets.
Nephrol Dial Transplant 2015 Aug
PMID:New developments concerning the proximal tubule in diabetic nephropathy: in vitro models and mechanisms. 2620 40