Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In experimental membranous nephropathy, C5b-9 induces noncytolytic glomerular epithelial cell (GEC) injury and proteinuria, which in some models is partially mediated by metabolites of arachidonic acid. In cultured GEC, sublytic C5b-9 increases cytosolic Ca2+ concentration ([Ca2+]i), activates phospholipase C (PLC), and releases arachidonic acid and eicosanoids. This study examined mechanisms of arachidonic acid production by C5b-9. In GEC labeled with [3H]arachidonate C5b-9 increased free [3H]arachidonic acid and 1,2-[3H]-arachidonoyl-diacylglycerol (DAG), an endogenous activator of protein kinase C (PKC). Elevated [Ca2+]i was not sufficient to account for increased free arachidonic acid. Moreover, in GEC that had been depleted of PKC by preincubation for 18 h with 2 microM phorbol myristate acetate, the C5b-9-induced arachidonate release was inhibited by greater than 75%. Reacylation of phospholipids was not decreased by C5b-9. Homogenates of GEC that had been stimulated with C5b-9 released more [14C]arachidonate from exogenously added 2-[14C]arachidonoyl-phosphatidyl-ethanolamine or 2-[14C]arachidonoyl-phosphatidylcholine than homogenates of unstimulated cells (assayed at a Ca2+ concentration of 2 mM). These experiments demonstrate directly that C5b-9 increased phospholipase A2 (PLA2) activity. PLA2 appeared to be stimulated as a result of PKC activation (probably secondary to increased DAG) in association with elevated [Ca2+]i. The C5b-9-induced activation of PLA2 may lead to release of eicosanoids, which may contribute toward impaired glomerular capillary wall permselectivity in experimental membranous nephropathy.
 ...
PMID:Release of arachidonic acid by complement C5b-9 complex in glomerular epithelial cells. 190 97

The glomerular synthesis of LTB4 was assessed in glomeruli isolated from rats with passive Heymann nephritis (PHN). PHN was induced by a single intravenous administration of proteinuric doses of immune sera raised in sheep against rat brush border tubular fraction Fx1A. At various time points following induction of the disease glomeruli were isolated and LTB4 synthesis was assessed under basal and phospholipase A2 activation conditions. LTB4 was measured by high pressure liquid chromatography and radioimmunoassay and was identified by UV spectroscopy. The role of complement system in mediating glomerular LTB4 synthesis was also assessed in a group of decomplemented rats using cobra venom factor and at various time points following administration of immune serum. Following induction of PHN, enhanced glomerular LTB4 synthesis was observed as early as one hour, peaked at five hours and returned toward control levels over the subsequent four days. The peak in glomerular LTB4 synthesis did not correlate with changes in glomerular neutrophiles or macrophages. A second increment of LTB4 synthesis occurred at the onset of heavy proteinuria (day 5). Complement depletion reduced proteinuria and the enhancement in LTB4 synthesis at day 5 but had no effect at earlier time points. The observations indicate that in non-inflammatory forms of glomerular immune injury the glomerular arachidonate 5-lipoxygenation is enhanced. This phenomenon has no apparent relationship with increased glomerular permeability to protein and may reflect the presence or activation of a leukotriene producing cell following intraglomerular interactions of Fx1A antigen, anti-Fx1A antibody and complement.
 ...
PMID:Glomerular leukotriene synthesis in Heymann nephritis. 255 84

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.
 ...
PMID:Platelet-activating factor and the kidney. 308 26

In rat membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which, in some models, is partially mediated by eicosanoids. By analogy, sublytic C5b-9 injures plasma membranes and releases arachidonic acid (AA) and eicosanoids in cultured rat GEC. In this study, we demonstrate that, in GEC, sublytic C5b-9 stably increased the activity of a high-molecular-mass cytosolic phospholipase A2 (PLA2), which we identified as "cPLA2." This increase was abolished with inhibitors of protein kinase C. C5b-9 did not affect low-molecular-mass membrane-associated or secretory PLA2 activities. In GEC that stably overexpress cPLA2 activity and protein (produced by transfection of cPLA2 cDNA), immunoblot analysis showed that sublytic C5b-9 induced a decreased mobility of cPLA2, consistent with cPLA2 phosphorylation. Incubation of cPLA2-transfected GEC with sublytic C5b-9 significantly increased production of free AA and prostaglandin E2, whereas, in control GEC, the C5b-9-induced changes in free AA and prostaglandin E2 were small. Furthermore, both C5b-9-dependent sublytic cytotoxicity and cytolysis were enhanced in GEC overexpressing cPLA2, compared with control cells. Thus C5b-9 increased cPLA2 activity, probably via phosphorylation involving a protein kinase C-dependent pathway. Phospholipid hydrolysis by cPLA2 resulted in release of substrate for eicosanoid synthesis and in enhancement of C5b-9-dependent GEC injury. Both processes may facilitate glomerular damage in membranous nephropathy.
 ...
PMID:Complement C5b-9 activates cytosolic phospholipase A2 in glomerular epithelial cells. 750 41

In rat membranous nephropathy, C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated by eicosanoids. In cultured rat GEC, sublytic C5b-9 injures plasma membranes and releases arachidonic acid (AA) and eicosanoids, due to activation of phospholipase A2 (PLA2). To address mechanisms of PLA2 activation, GEC were stably transfected with cDNAs of wild-type cytosolic PLA2 (cPLA2-wt), or group II secretory PLA2, producing overexpression of PLA2 activity. Sublytic C5b-9 markedly increased free [3H]AA in cPLA2-wt-transfected GEC, but only trivial increases were evident in secretory PLA2-transfected, or neo (control) GEC. In cPLA2-wt-transfected GEC, reduction of extracellular free Ca2+ or down-regulation of protein kinase C inhibited [3H]AA release. To further address the regulation of cPLA2, we stably expressed a mutant cPLA2 in which the Ca2+-dependent lipid binding domain was deleted (deltaCaLB). In GEC that express cPLA2-deltaCaLB, the C5b-9-induced increase in free [3H]AA was comparable with neo, despite expression of cPLA2-deltaCaLB at levels similar to cPLA2-wt. We then stably expressed another cPLA2 mutant (cPLA2-srcmyr) in which the CaLB domain was replaced by the N-terminal myristoylation domain of c-Src. cPLA2-srcmyr is permanently membrane associated. At low extracellular free Ca2+, C5b-9 increased free [3H]AA significantly in GEC that express cPLA2-srcmyr, while in neo GEC, the change was negligible. Thus, C5b-9 activates the cPLA2 isoform. Activation is dependent on the CaLB domain, and is mediated by phosphorylation, Ca2+ influx, and membrane association.
 ...
PMID:Activation of phospholipase A2 by complement C5b-9 in glomerular epithelial cells. 931 58

The venom of Bothrops moojeni has potent proteolytic and phospholipase A2 activities. In previous work, we showed that intravenous injection of this venom in rats decreased creatinine clearance and caused tubular dysfunction and histopathological changes with no alterations in blood pressure. The current study used scanning and transmission electron microscopy to assess the ultrastructural changes caused by B. moojeni venom (0.4 mg/kg i.v.) in rat renal glomeruli and correlated these alterations with the severity of proteinuria 5 hours, 16 hours, and 48 hours after venom injection. The changes included mesangiolysis, glomerular microaneurysms, and glomerular basement membrane (GBM) abnormalities. In addition, there was a reduction in the number and width of podocyte pedicels, which caused a reduction in the number of filtration slits. Electron-dense amorphous material, which may be proteinaceous in origin, was found in the pedicels. The severity of the ultrastructural abnormalities correlated with the level of proteinuria. These morphophysiological changes were attributed to biochemical and physiological disturbances in the components of the GBM and mesangial matrix as well as in cytoskeleton-associated proteins of podocytic processes, and could account for the breakdown of optimal glomerular filtration barrier functioning. These results, together with the absence of appreciable glomerular fibrin deposits, support the hypothesis of a direct activity of B. moojeni venom on rat kidneys. Proteolytic activity of the venom on renal glomeruli could then contribute to the onset of acute renal failure, and would explain the clinical manifestations of renal injury after bites by this and other Bothrops species.
 ...
PMID:Bothrops moojeni snake venom-induced renal glomeruli changes in rat. 1238 51

Radiation-induced renal injury is characterized by proteinuria, hypertension, and progressive decline in renal function. We have previously shown that in vivo or in vitro irradiation of glomeruli with a single dose of radiation (9.5 Gy) increases glomerular albumin permeability (P(alb)) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in P(alb) is caused by the release of arachidonic acid and by the generation of specific arachidonic acid metabolites. Glomeruli obtained from WAG/Rij/MCW rats and cultured rat glomerular epithelial and mesangial cells were studied after irradiation (9.5 Gy, single dose). Arachidonic acid release and eicosanoid synthesis by glomeruli or cultured glomerular cells were measured after irradiation, and the effect of inhibitors of phospholipase A2 (PLA2) and cyclooxygenase (COX) on the irradiation-induced increase in P(alb) was assessed. Arachidonic acid release was demonstrated within 10 mins of irradiation of isolated glomeruli and monolayer cultures of glomerular epithelial and mesangial cells. Prostaglandin F(2alpha) (PGF(2alpha)) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in P(alb). COX inhibition immediately after irradiation also diminished the radiation-induced increase in P(alb). We conclude that arachidonic acid and its COX metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P(alb). Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.
 ...
PMID:Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability. 1638 Jun 50

Membranous nephropathy (MN) is the most common cause for nephrotic syndrome in adults and occurs as an idiopathic (primary) or secondary disease. Since the early 2000's, substantial advances have been made in the understanding of the molecular bases of MN. The neutral endopeptidase (NEP) and the receptor for secretory phospholipase A2 (PLA2R) have been identified as target antigens for circulating and deposited antibodies in allo-immune neonatal and adult " idiopathic " MN, respectively. These antibodies recognize specific antigens of podocytes, precipitate as subepithelial immune complexes and activate complement leading to proteinuria. Anti-PLA2R antibodies are of particular clinical importance. Indeed, they are detected in approximately 70% of primary MN in adults, demonstrating that MN actually is an autoimmune condition specific to the kidney. In Europeans, genome-wide studies have shown an association between alleles of PLA2R1 and HLA DQA1 (class II genes of tissue histocompatibility complex) genes and idiopathic MN. Newly developed diagnostic tests detecting circulating anti-PLA2R antibody and PLA2R antigen in glomerular deposits have induced a change in paradigm in the diagnostic approach of idiopathic MN. Measurement of circulating anti-PLA2R antibody is also very useful for the monitoring of MN activity. However, the mechanisms responsible for the formation of anti-PLA2R antibodies as well as those involved in the progression of MN to end-stage renal disease remain to be defined.
 ...
PMID:[Anti-NEP and anti-PLA2R antibodies in membranous nephropathy: an update]. 2637 79

Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in native kidney biopsies from adults. In 2009, antibodies to the M-type receptor of phospholipase A2 (anti-PLA2R) were identified in idiopathic MN patients, both within the kidney and in the circulation. The clinical course of idiopathic MN is variable and ranges from spontaneous remission to end-stage renal disease. Clinical variables such as proteinuria levels, patient sex, age and renal function at diagnosis have been associated with renal MN progression. In this editorial, we update the importance of anti-PLA2R levels as a prognostic marker in idiopathic MN at the diagnosis of the disease.
 ...
PMID:Anti-phospholipase A2 receptor antibody and spontaneous remission in membranous nephropathy. 3074 49

Membranous nephropathy (MN), an autoimmune glomerulonephritis which can occur in primary and secondary forms, is one of the most common inflammatory glomerulopathies in elderly patients. The pathophysiology of the primary form is generally due to circulating immunoglobulin (IgG4) antibodies which often target phospholipase A2 receptors (anti-PLA2R) and Thrombospondin Type 1 Domain containing 7A (anti THSD7A). IgA nephropathy is one of the most common autoimmune glomerular diseases in the world and presents with a spectrum of disease ranging from asymptomatic mild hematuria and proteinuria to rapidly progressive crescentic glomerulonephritis. We present a rare case of concomitant IgA and primary MN in a single patient treated successfully with renin-angiotensin-aldosterone blockade, corticosteroids, and calcineurin inhibitors. The peak proteinuria was near 7.5-8 g protein/g creatinine by various measures. Serum creatinine remained normal, and anti-PLA2R was detectable and decreased with successful treatment. Clinicians should be aware of the possibility of two glomerular disorders in patients with glomerulonephritis and atypical presentations for any single disorder.
 ...
PMID:Primary membranous nephropathy with concomitant IgA nephropathy. 3103 92


1 2 Next >>