UMLS:C0033687 - FACTA Search

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)

This Review summarizes recent research on the podocyte slit diaphragm. A growing number of molecules that function at the slit diaphragm have been identified in patients with inherited and sporadic nephrotic syndromes. Genetic deletion of nearly all of these molecules results in proteinuria and effacement of foot processes. Nephrin, Neph1 and podocin seem to form a multifunctional receptor complex at the slit diaphragm. Most of the other components of the slit diaphragm interact directly with this complex, in many cases coupling slit diaphragm components to the podocyte's actin cytoskeleton. These molecular findings are being applied to patients with glomerular disease. Over the next decade, these data might help to improve disease classification and prediction of which patients will respond to immunosuppressive treatment.
...
PMID:Clinical impact of research on the podocyte slit diaphragm. 1693 40

There have been many exciting advances in our understanding of genetic causes of nephrotic syndrome since 1998 when nephrin was first found. The mRNA expressions of nephrin and CD2AP were studied by quantitative real-time polymerase chain reaction (PCR) in aspirated renal biopsy tissues from 9 subjects with minimal change nephrotic syndrome (MCNS), 6 with primary IgA nephropathy (IgAN), and 15 controls. Protein expression of nephrin, podocin, and CD2AP were analyzed by immunohistochemistry, indirect immunofluorescence, and laser confocal microscope. Compared with controls, the CD2AP mRNA level was significantly downregulated in renal samples from MCNS and IgAN patients (p=0.001 in MCNS, p=0.046 in IgAN), though no significant downregulation was found in the mRNA level of nephrin (p=0.346 in MCNS, p=0.311 in IgAN). The expression levels of protein CD2AP and nephrin were significantly reduced in MCNS and IgAN (MCNS: nephrin, p=0.034, CD2AP, p=0.005; IgAN: nephrin, p=0.021, CD2AP, p=0.025). The podocin staining did not differ significantly between controls and disease groups (p value 0.340 and 0.787, respectively). The results suggest that transcript and translation expression changes of nephrin and CD2AP may have pathogenetic roles in some patients with MCNS and IgAN in Chinese, though no correlation was found in podocin with proteinuria in this study.
...
PMID:Expression profile of nephrin, podocin, and CD2AP in Chinese children with MCNS and IgA nephropathy. 1694 Nov 46

Posttransplantation recurrence of focal segmental glomerulosclerosis (FSGS) is one of the most disarming events in human pathology with important social and psychological consequences. It usually occurs in 30% to 50% of patients affected by the primary form of the disease with an abrupt onset in the majority of cases occurring within 1 month of the transplantation. Prediction of recurrent cases and early therapy with plasmapheresis are the main goals of the therapy. Although the mechanism of posttransplantation recurrence is still obscure, it has been proposed to be of a multifactorial origin, in which plasma factors determine the shedding of proteins of the slit-diaphragm, such as nephrin and podocin, with structural alterations of the ultra-filtering unit of the glomerulus. Low resynthesis of podocin and/or haplo-insufficiency due to heterozygous mutations should represent significant predisposing factors to proteinuria. In this review, the role of podocin in posttransplantation recurrence will be evaluated focusing on the possibility that resynthesis of the protein could represent a key step also for stable normalization of the renal filter. The recent characterization of the podocin promoter cis- and trans- acting elements and the possibility to characterize low- and high-podocin producer haplotypes offer opportunities to evaluate the capacity for podocin resynthesis in the donor kidney. A review of the literature on posttransplantation recurrence of FSGS in patients originally carrying homozygous and/or heterozygous NPHS2 mutations supports the general idea of a multifactorial origin of the primary disease that can be extended to the pathogenesis of posttransplantation recurrence.
...
PMID:Podocin-related mechanisms in posttransplant [corrected] recurrence of focal segmental glomerulosclerosis [corrected]. 1717 12

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1-infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RARalpha is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1-transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1-infected podocytes by stimulating RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.
...
PMID:Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. 1718 84

Accumulating evidence suggests that mineralocorticoid receptor blockade effectively reduces proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with aldosterone and fed a high-salt diet. Aldosterone induced proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules nephrin and podocin were markedly decreased in aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of aldosterone effector kinase Sgk1. Treatment with eplerenone, a selective aldosterone receptor blocker, almost completely prevented podocyte damage and proteinuria, with normalization of elevated reduced nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition, proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by tempol, a membrane-permeable superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although hydralazine treatment almost normalized blood pressure, it failed to improve proteinuria and podocyte damage. In cultured podocytes with consistent expression of mineralocorticoid receptor, aldosterone stimulated membrane translocation of reduced nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore, aldosterone enhanced the expression of Sgk1, which was inhibited by mineralocorticoid receptor antagonist and tempol. In conclusion, podocytes are injured at the early stage in aldosterone-infused rats, resulting in the occurrence of proteinuria. Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.
...
PMID:Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1. 1720 Apr 34

Recent discoveries indicate that the molecules in glomerular podocytes and slit diaphragms may play an important role in the development of proteinuria and nephrotic syndrome. Mutational analyses of NPHS1 and NPHS2 were performed to verify this hypothesis in sporadic nephrotic syndrome (NS) patients. Clinical characteristics and DNA samples were collected from 38 Chinese children with sporadic steroid-sensitive NS, 22 with steroid-resistant NS and 30 controls. Direct sequencing was performed after PCR amplification of all 29 and 8 exons of the NPHS1 and NPHS2 genes, respectively. In NPHS1, 4 patients had heterozygous missense mutations leading to amino acid substitutions (R800C, Q453R). Furthermore, 3 known single nucleotide polymorphism (SNP) were found (T741T, V763V, S1105S). In NPHS2, 3 patients had novel heterozygous allelic variants leading to amino acid substitutions (S206I, E188D), while 1 patient was found to carry a novel nonsense mutation leading to a truncated protein product (Glu237STOP). Two known polymorphisms were also found (A318A, L346L). The results demonstrate that NPHS1 and NPHS2 mutations are also present in Chinese sporadic NS patients, suggesting that genetic changes of nephrin and podocin may play pathogenetic roles in some patients with sporadic steroid resistant NS.
...
PMID:NPHS1 and NPHS2 gene mutations in Chinese children with sporadic nephrotic syndrome. 1721 Nov 52

HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.
...
PMID:Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. 1722 13

Inherited forms of proteinuria constitute a rare and heterogeneous group of diseases, the most prominent of which is glomerular dysfunction, which leads to proteinuria. Investigation of the genetic background underlying these diseases has provided significant data on the normal operation of the glomerular filter. Among the different components of the glomerulus, the podocyte slit diaphragm is considered the main source for genetically derived protein alteration, which leads in turn to proteinuria. Investigation of the different proteins revealed that the lack of nephrin and podocin is the leading cause of several inherited forms of proteinuria. It was also proposed that the lack of podocin is linked to cardiac anomalies. This review suggests that the absence of slit diaphragm proteins and the open zipper phenomenon are associated with cardiac anomalies.
...
PMID:Renal slit diaphragm--the open zipper and the failing heart. 1734 83

IL-13 has been implicated in the pathogenesis of minimal-change nephrotic syndrome. This study aimed to investigate the role of IL-13 on the development of proteinuria and expression of podocyte-related genes that are associated with nephrotic syndrome. IL-13 was overexpressed in Wistar rats through transfection of a mammalian expression vector cloned with the rat IL-13 gene, into the quadriceps by in vivo electroporation. Serum IL-13, albumin, cholesterol, and creatinine and urine albumin were measured serially. Kidneys were harvested after day 70 for histology and electron microscopy. Glomerular gene expression of nephrin, podocin, dystroglycan, B7-1, and IL-13 receptor subunits were examined using real-time PCR with hybridization probes and expressed as an index against beta-actin. Protein expression of these molecules was determined by immunofluorescence staining. The IL-13-transfected rats (n = 41) showed significant albuminuria, hypoalbuminemia, and hypercholesterolemia when compared with control rats (n = 17). No significant histologic changes were seen in glomeruli of IL-13-transfected rats. However, electron microscopy showed up to 80% of podocyte foot process fusion. Glomerular gene expression was significantly upregulated for B7-1, IL-4Ralpha, and IL-13Ralpha2 but downregulated for nephrin, podocin, and dystroglycan. Immunofluorescence staining intensity was reduced for nephrin, podocin, and dystroglycan but increased for B7-1 and IL-4Ralpha in IL-13-transfected rats compared with controls. In conclusion, these results suggest that IL-13 overexpression in the rat could lead to podocyte injury with downregulation of nephrin, podocin, and dystroglycan and a concurrent upregulation of B7-1 in the glomeruli, inducing a minimal change-like nephropathy that is characterized by increased proteinuria, hypoalbuminemia, hypercholesterolemia, and fusion of podocyte foot processes.
...
PMID:Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. 1742 54

Serial changes in glomerular capillary loop gene expression were used to uncover mechanisms contributing to primary glomerular disease in rat models of passive Heymann nephritis and puromycin nephrosis. Before the onset of proteinuria, podocyte protein-tyrosine phosphatase (GLEPP1) expression was transiently decreased in the nephrosis model, whereas the immune costimulatory molecule B7.1 was stimulated in both models. To relate these changes to the development of proteinuria, the time of onset and intensity of proteinuria were altered. When the models were induced simultaneously, proteinuria and anasarca occurred earlier with the collapse of glomerular capillary loops. Upregulation of B7.1 with the downregulation of GLEPP1, Wilms' tumor gene (WT1), megalin, and vascular endothelial growth factor started early and persisted through the course of disease. In the puromycin and the combined models, changes in GLEPP1 expression were corticosteroid-sensitive, whereas B7.1, WT1, vascular endothelial growth factor, and most slit diaphragm genes involved later in the combined model, except podocin, were corticosteroid-resistant. There was a very early increase in the nuclear expression of podocyte transcription factors ZHX2 and ZHX1 that may be linked to the changes in gene expression in the combined proteinuric model. Our studies suggest that an early and persistent change in mostly steroid-resistant glomerular gene expression is the hallmark of severe and progressive glomerular disease.
...
PMID:Early changes in gene expression that influence the course of primary glomerular disease. 1745 73

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>