Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor of activated T cells (NFAT) originally was identified as a T-cell-specific transcription factor whose activity is regulated by calcineurin, one of the serine-threonine phosphatases. Recent studies have shown that NFAT also is expressed in nonlymphoid cells and plays an important role in various cell functions. It is widely known that treatment with cyclosporin A (CsA), which can inhibit calcineurin/NFAT signaling, results in glomerular dysfunction characterized by a decrease of GFR or glomerulosclerosis, suggesting that NFAT might regulate the glomerular function. However, the precise function of NFAT in glomerular cells remains to be clarified. Herein, evidence has been produced that NFAT2/NFATc, one of five known NFAT isoforms, is expressed in glomerular mesangial cells. Stimulation of mesangial cells with endothelin-1 caused translocation of NFAT2 into the nucleus with a concomitant increase in NFAT2 DNA-binding activity, both of which were inhibited by CsA. Furthermore, CsA inhibited endothelin-1-induced cyclooxygenase-2 (COX-2) expression in mesangial cells. NFAT2 bound directly to the GGAAA sequence, which is the minimal consensus sequence for NFAT binding, in a promoter region of rat COX-2 gene, and it enhanced the reporter activity of rat COX-2 promoter in mesangial cells. These findings provide the first evidence that NFAT2 is expressed and regulates COX-2 gene expression in mesangial cells. These results will contribute to evaluation of the precise roles of NFAT in glomerular functions and the CsA-induced nephrotoxicity.
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PMID:Endothelin-1 induces cyclooxygenase-2 expression via nuclear factor of activated T-cell transcription factor in glomerular mesangial cells. 1142 65

Within the last 5 years, dramatic changes in the area of renal transplantation have occurred. There have been shifts in the dominant types of rejection, and in the types and utilization of immunosuppressants. Hyperacute rejection is now rarely seen, and acute cellular rejection within the first 6 to 12 months has been reduced to about 10%. However, humoral/antibody-mediated rejection has become a more prevalent problem. In the area of immunosuppressants, the ability to reduce acute cellular rejection to about 10% has been achieved through more judicious use of calcineurin inhibitors (cyclosporine and tacrolimus), increased use of mycophenolate mofetil, and the recent introduction of sirolimus (rapamycin). The polyclonal antibody (antithymocyte globulin), as well as monoclonal antibodies directed against the alpha chain of CD25 (daclizumab and basilixamab), have added substantially to the improved success of renal allografts. Because of numerous serious toxicities from glucocorticoids and calcineurin inhibitors, particularly cyclosporine, new studies are utilizing calcineurin-free and/or glucocorticoid avoidance or rapid elimination protocols often in combination with a monoclonal antibody and sirolimus. New immunosuppressants such as FTY720 and Campath-1 are also under study. In addition to its use in treating patients with low-level donor-specific antibody before transplantation in order to avoid hyperacute rejection, apheresis is utilized in various combination protocols after transplantation in the management of humoral/antibody-mediated rejection, in the treatment of hemolytic uremia syndrome that sometimes occurs with calcineurin inhibitors and sirolimus, as well as in the treatment of focal segmental glomerulosclerosis that has a major risk of recurrence in renal transplants.
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PMID:Renal transplantation: basic concepts and evolution of therapy. 1456 8

The transition of normally quiescent glomerular MCs (mesangial cells) to a highly proliferative phenotype with characteristics of myofibroblasts is a process commonly observed in inflammatory diseases affecting the renal glomerulus, the ultimate result of which is glomerulosclerosis. Generation of proteolytically active MMP (matrix metalloproteinase)-2 by the membrane-associated membrane type 1 (MT1)-MMP is responsible for the transition of mesangial cells to the myofibroblast phenotype [Turck, Pollock, Lee, Marti and Lovett (1996) J. Biol. Chem. 271, 15074-15083]. In the present study, we show that the expression of MT1-MMP within the context of MCs is mediated by three discrete cis -acting elements: a proximal non-canonical Sp1 site that preferentially binds Sp1; an overlapping Sp1/Egr-1-binding site that preferentially binds Egr-1; and a more distal binding site for the NFAT (nuclear factor of activated T cells) that binds the NFAT c1 isoform present in MC nuclear extracts. Transfection with an NFAT c1 expression plasmid, or activation of calcineurin with a calcium ionophore, yielded major increases in NFAT c1 nuclear DNA-binding activity, MT1-MMP transcription and protein synthesis, which were additive with the lower levels of transactivation provided by the proximal Sp1 and the overlapping Sp1/Egr-1 sites. Specific binding of NFAT c1 to the MT1-MMP promoter was confirmed by chromatin immunoprecipitation studies, while MT1-MMP expression was suppressed by treatment with the calcineurin inhibitor, cyclosporin A. These studies are the first demonstration that a specific NFAT isoform enhances transcription of an MMP (MT1-MMP) that plays a major role in the proteolytic events that are a dominant feature of acute glomerular inflammation. Suppression of MT1-MMP by commonly used calcineurin inhibitors may play a role in the development of renal fibrosis following renal transplantation.
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PMID:Co-operative interactions between NFAT (nuclear factor of activated T cells) c1 and the zinc finger transcription factors Sp1/Sp3 and Egr-1 regulate MT1-MMP (membrane type 1 matrix metalloproteinase) transcription by glomerular mesangial cells. 1497 75

Recurrence of the initial renal disease after kidney transplantation is a major cause of graft dysfunction and failure. Glomerulopathies are reported to account for 80% of such cases, but this figure should be interpreted with care, as extensive investigations (immunofluorescence or electron microscopy studies of the explanted kidney) are needed to prove that the initial disease has indeed recurred and to determine prevalence rates. In the following order of frequency, focal segmental glomerulosclerosis, membranous glomerulonephritis, mesangiocapillary glomerulonephritis and IgA nephropathy have a tendency to recur, while, surprisingly, anti-glomerular basement membrane nephritis and systemic lupus erythematosus are less likely to relapse on the donor kidney. There is no evidence that anti-calcineurin therapy has any impact on the risk of recurrence. Options for the prevention and treatment of these recurrences are very limited, calling for very cautious use of living familial donors.
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PMID:[Recurrent kidney disease and its prevention after renal transplantation. Review of the literature]. 1565 30

Liver transplant recipients are at risk of chronic renal failure (CRF), customarily considered to be secondary to CsA/FK506 nephrotoxicity. We have examined renal biopsies from 26 liver transplant recipients with CRF. Before OLT, 5 patients had CRF, 8 were diabetic and 9 hypertensive. Renal biopsies were performed at a mean of 5 years after liver transplantation. Mean SCr was then 212 micromol/L, proteinuria was 1 g/24 h. Twelve patients were diabetic and 25 hypertensive. Histology revealed impressive renal destruction, with a mean of 45% interstitial fibrosis and 45% glomerular sclerosis. All biopsies showed severe arteriosclerosis. CRF can be attributed to four associated primary lesions: (i) specific chronic CsA/FK506 arteriolopathy; (ii) typical diabetic nephropathy; (iii) acute or chronic thrombotic microangiopathy attributed to CsA/FK506 or alpha-IFN and (iv) tubular changes related to administration of hydroxyethylstarch. At the end of the follow-up, after a mean of 6.4 years, 12 patients required dialysis, 13 had CRF and only 1 had normal renal function. Thus, CRF in OLT recipients is more complex than originally thought and should not be classified as anti-calcineurin nephrotoxicity without further investigations, including renal histology. These investigations have therapeutic potential, that is, they may lead to a more aggressive treatment of hypertension and/or diabetes.
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PMID:Renal histopathological lesions after orthotopic liver transplantation (OLT). 1581 74

The aim of this study was to investigate whether glomerular sclerosis (GS) at the time of engraftment affects subsequent morphology and clinical course of renal allografts. Eighty-one renal transplant recipients were recruited for this study. Protocol biopsies of the renal allografts were performed at engraftment, as well as at 1, 3, 5, and 7 years after transplantation. All cases were divided into 2 groups based on the presence of GS at engraftment, namely, non-GS and GS groups. Morphological changes in the renal allografts were graded from 0 to 3+ based on the severity of chronic allograft nephropathy (CAN) of the Banff classification based on 5 factors: percentage of GS, extent of interstitial fibrosis, tubular atrophy, arterial intimal thickening, and arteriolar hyalinosis. Furthermore, the level of serum creatinine (s-Cr) at each year was examined by recipient age and gender, donor age and gender, type of donor (living/cadaver), delayed graft function, acute rejection within 1 year after transplantation, mean blood pressure, and use of calcineurin inhibitors as well as the presence of GS at engraftment. The extent of GS at engraftment significantly correlated with donor age (P = .0038) but with a weak correlation coefficient. Although the severity of CAN developed gradually in both non-GS and GS groups, differences in morphological changes at engraftment between the 2 groups persisted throughout 7 years. Donor age and recipient gender influenced s-Cr significantly. In conclusion, the presence of GS at engraftment aggravates subsequent morphological changes and affects short-term but not long-term allograft prognosis.
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PMID:Baseline glomerular sclerosis influences morphological changes, but not level of serum creatinine. 1584 9

The major causes of renal transplant loss are death from vascular, malignant or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Chronic allograft nephropathy (CAN) is the histologic description of the fibrosis, vascular and glomerular damage occurring in renal allografts. Clinical programs rely on monitoring change in serum creatinine for identification of patients at risk of CAN, but this change occurs late in the course of the disease, and underestimates the severity of pathologic change. CAN has several causes: ischemia-reperfusion injury, ineffectively or untreated clinical and subclinical rejection, and superimposed calcineurin inhibitor nephrotoxicity, exacerbating pre-existing donor disease. Once established, interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerulosclerosis over the subsequent years. There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients. These immunosuppression strategies combine corticosteroids with azathioprine or mycophenolate mofetil, and/or sirolimus and everolimus. Late identification of CAN in individual patients has meant that strategies for intervening to prevent chronic renal allograft dysfunction and subsequent graft loss tend to be "too little and far too late."
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PMID:Chronic renal allograft dysfunction. 1612 Aug 19

Insulin-like growth factor (IGF)-1 is accumulated in the diabetic kidney and is considered to be involved in the development of glomerular sclerosis. Here, we investigate IGF-1 regulation of laminin, an extracellular matrix (ECM) component, and cyclin D1 and p21Cip1, cell-cycle progression factor, expressions in glomerular mesangial cells. We show that IGF-1 increases the level of laminin gamma1 and beta1 subunits approximately 1.5- and 2.5-fold, respectively, in a time-dependent manner. IGF-1 also stimulates protein kinase Akt/PKB phosphorylation at Thr 308, which correlates with its activity, up to 24 h. The Akt activation is coupled with Ser 9 phosphorylation of its downstream target, glycogen synthase kinase-3beta (GSK-3beta), which inhibits its kinase activity. Laminin beta1 is reduced significantly (P < 0.03) by inhibitors of Akt and p38MAPK whereas laminin gamma1 is not affected. Surprisingly, IGF-1 activates the expression of both cyclin D1 and cell-cycle arrest factor, p21Cip1 parallely. Pharmacological inhibition of calcineurin by cyclosporin A blocks IGF-1-induced cyclin D1 and p21Cip1expression significantly (P < 0.05). IGF-1 enhances cellular metabolic activity and viability of rat mesangial cells; however, they are arrested at the G1 phase of cell cycle as revealed by the FACS analysis. These results indicate that IGF-1 mediates mesangial cell-cycle progression, hypertrophy, and ECM protein synthesis. The Akt/GSK-3beta, p38MAPK, and calcineurin pathways may play an important role in IGF-1 signaling, cell-cycle regulation, and matrix gene expression in mesangial cells leading to the development of diabetic glomerulopathy.
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PMID:IGF-1 increases laminin, cyclin D1, and p21Cip1 expression in glomerular mesangial cells: an investigation of the intracellular signaling pathway and cell-cycle progression. 1640 77

Chronic Allograft Nephropathy (CAN) is one of the most common cause of kidney transplant loss. CAN may be caused by immunologic as well as nonimmunologic factors which may interfere and increase response. Immunologic factors include acute rejection, degree of HLA mismatch, inadequate immunosuppression. Nonimmunologic factors contain delayed graft function, ischemia-reperfusion injury, nephrotoxicity of calcineurin inhibitors, hyperfiltration, hypertension and hyperlipidemia. The histopatological description of CAN may indicate two phases of injury. An initial phase by one year include tubulointerstitial infiltration in the late phase of CAN arteriolar hyalinosis and glomerulosclerosis were revealed. Modification of the immunosuppressive treatment with reduction or withdrawal of calcineurin inhibitors may prevent graft loss, while addition of nonnephrotoxic agents such as mycophenolate mofetil or sirolimus should be considered by the risk of acute rejection. Additionally effective management by hypertension and hyperlipidemia is essential.
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PMID:Chronic allograft nephropathy--immunologic and nonimmunologic factors. 1702 23

Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 +/- 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 +/- 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.
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PMID:Proteinuria in transplant patients associated with sirolimus. 1736 56


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