Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic kidney disease (CKD) is estimated to affect one in eight adults. Their kidney function progressively deteriorates as inflammatory and fibrotic processes damage nephrons. New therapies to prevent renal functional decline must build on basic research studies that identify critical cellular and molecular mediators. Plasminogen activator inhibitor-1 (PAI-1), a potent fibrosis-promoting glycoprotein, is one promising candidate. Absent from normal kidneys, PAI-1 is frequently expressed in injured kidneys. Studies in genetically engineered mice have demonstrated its potency as a pro-fibrotic molecule. Somewhat surprising, its ability to inhibit serine protease activity does not appear to be its primary pro-fibrotic effect in CKD. Both tissue-type plasminogen activator and plasminogen deficiency significantly reduced renal fibrosis severity after ureteral obstruction, while genetic urokinase (uPA) deficiency had no effect. PAI-1 expression is associated with enhanced recruitment of key cellular effectors of renal fibrosis - interstitial macrophages and myofibroblasts. The ability of PAI-1 to promote cell migration involves interactions with the low-density lipoprotein receptor-associate protein-1 and also complex interactions with uPA bound to its receptor (uPAR) and several leukocyte and matrix integrins that associate with uPAR as co-receptors. uPAR is expressed by several cell types in damaged kidneys, and studies in uPAR-deficient mice have shown that its serves a protective role. uPAR mediates additional anti-fibrotic effects - it interacts with specific co-receptors to degrade PAI-1 and extracellular collagens, and soluble uPAR has leukocyte chemoattractant properties. Molecular pathways activated by serine proteases and their inhibitor, PAI-1, are promising targets for future anti-fibrotic therapeutic agents.
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PMID:Serine proteases, inhibitors and receptors in renal fibrosis. 1935 Jan 8

Chronic kidney disease (CKD), defined as a decreased estimated glomerular filtration rate (eGFR < 60 ml/min), is an independent risk factor for cardiovascular events. Both acute coronary syndrome (ACS) and end-stage renal disease have been shown to be associated with formation of compact fibrin clots relatively resistant to lysis. The aim of the current study was to evaluate the effect of CKD on fibrin clot properties in patients with ACS. In 30 ACS patients, aged 48-72 years, with CKD and 30 ACS patients with eGFR more than 60 ml/min, we investigated plasma fibrin clot properties using permeation and turbidity assays, including three different clot lysis assays. The ACS patients with eGFR less than 60 ml/min and those with normal filtration rate did not differ with regard to demographics, risk factors, medications and routine laboratory tests, including fibrinogen. The former group had higher plasminogen activator inhibitor-1 (P = 0.002) and tissue-type plasminogen activator (tPA) (P = 0.008). Compared with ACS patients with eGFR more than 60 ml/min, the ACS patients with CKD formed less porous fibrin clots (P = 0.004) and susceptible to fibrinolysis (P < 0.001), had thicker overall fibrin fibers (P = 0.007), earlier onset of fibrin clot formation (P = 0.004) and increased clot mass (P < 0.001). By multiple regression analysis, clot permeability was independently predicted by eGFR (P = 0.0005) and fibrinogen (P = 0.001), whereas the only predictors of lysis time were eGFR (P = 0.006) and tPA (P = 0.002). This study indicates that ACS patients with CKD display unfavorable fibrin clot properties including impaired fibrinolysis, which might contribute to worse outcome in this population.
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PMID:The effect of chronic kidney disease on fibrin clot properties in patients with acute coronary syndrome. 2047 39

Chronic kidney disease (CKD) is common, affecting about 10% of the general population, and causing significant morbidity and mortality. Apart from the risk conferred by traditional cardiovascular risk factors, there is a strong genetic component. The method of a genome-wide association study (GWAS) is a powerful hypothesis-free approach to unravel this component by association analyses of CKD with several million genetic variants distributed across the genome. Since the publication of the first GWAS in 2005, this method has led to the discovery of novel loci for numerous human common diseases and phenotypes. Here, we review the recent successes of meta-analyses of GWAS on renal phenotypes. UMOD, SHROOM3, STC1, LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2/SH2B3, DACH1, UBE2Q2, and SLC7A9 were uncovered as loci associated with estimated glomerular filtration rate (eGFR) and CKD, and CUBN as a locus for albuminuria in cross-sectional data of general population studies. However, less than 1.5% of the total variance of eGFR and albuminuria is explained by the identified variants, and the relative risk for CKD is modified by at most 20% per locus. In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA(2)R1 implicate most of the risk for idiopathic membranous nephropathy. In contrast, genetic findings in the analysis of diabetic nephropathy are inconsistent. Uncovering variants explaining more of the genetically determined variability of kidney function is hampered by the multifactorial nature of CKD and different mechanisms involved in progressive CKD stages, and by the challenges in elucidating the role of low-frequency variants. Meta-analyses with larger sample sizes and analyses of longitudinal renal phenotypes using higher-resolution genotyping data are required to uncover novel loci associated with severe renal phenotypes.
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PMID:Chronic kidney disease: novel insights from genome-wide association studies. 2169 Nov 25