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

Mice lacking CD2-associated protein (CD2AP-/-) develop glomerular lesions resembling human focal segmental glomerulosclerosis (FSGS) between 3-4 weeks of age and die approximately 2 weeks later from massive proteinuria and renal failure. The mechanisms involved in the glomerular injury in this model are unclear. In this study, we used laser capture microdissection (LCM) and real-time PCR, and examined expression of TGF-ss isoforms in CD2AP-/- mice at the level of isolated glomeruli. Total RNA yield from cryosections of 30 glomeruli was 10.71 ng (SD, 5.45) in CD2AP+/+ group (n =7), and 4.20 ng (SD, 2.04) in CD2AP-/- group (n =8), p =0.008. Expression of TGF-ss1 mRNA was increased 1.5-fold in the whole kidney (p =0.030), and twofold in isolated CD2AP-/- glomeruli (p =0.026). Whole kidney mRNA of TGF-ss receptor I (RI) and II (RII) was not different in CD2AP-/- and CD2AP+/+ animals, but it was increased in CD2AP-/- glomerular samples by 4.38-fold (p =0.001) and 11.37-fold (p =0.0163), respectively. By using LCM we confirmed increased glomerular expression levels of TGF-ss isoforms previously described by our group in glomeruli isolated by sieving in CD2AP KO mice and underscored the importance of local factors in the development of glomerulosclerosis.
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PMID:Glomerular expression of transforming growth factor-beta (TGF-beta) isoforms in mice lacking CD2-associated protein. 1638 93

Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular diagnosis resulting in end-stage renal disease. Defects in several podocyte proteins have been implicated in the etiology of FSGS, including podocin, alpha-actinin-4, CD2-associated protein (CD2AP), and TRPC6. Despite our growing understanding of genes involved in the pathogenesis of focal segmental sclerosis, the vast majority of patients with this disease, even those with a familial linkage, lack a clear genetic diagnosis. Here, we tested whether combinations of genetic heterozygosity (bigenic heterozygosity) that alone do not result in clinical kidney disease could function together to enhance susceptibility to glomerular damage and FSGS. Combinations of Cd2ap heterozygosity and heterozygosity of either synaptopodin (Synpo) or Fyn proto-oncogene (Fyn) but not kin of IRRE like 1 (Neph1) resulted in spontaneous proteinuria and in FSGS-like glomerular damage. These genetic interactions were also reflected at a functional level, as we found that CD2AP associates with Fyn and Synpo but not with Neph1. This demonstrates that bigenic heterozygosity can lead to FSGS and suggests that combined mutations in 2 or multiple podocyte genes may be a common etiology for glomerular disease.
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PMID:Bigenic mouse models of focal segmental glomerulosclerosis involving pairwise interaction of CD2AP, Fyn, and synaptopodin. 1662 51

Nephrin, podocin, CD2AP, and alpha-actinin-4 are important podocyte proteins that help maintain the integrity of the slit diaphragm and prevent proteinuria. Studies have shown that angiotensin-converting enzyme inhibitors, glucocorticoids, and all-trans retinoic acid (ATRA) have antiproteinuric effects. However, it is still unclear whether these drugs, with different pharmacological mechanisms, lead to a reduction in proteinuria by changing the expression and distribution of these important podocyte proteins. In this study, changes in the expression and distribution of nephrin, podocin, CD2AP, and alpha-actinin-4 were dynamically detected in Adriamycin-induced nephrotic (ADR) rats treated with three different drugs: lisinopril, prednisone, and ATRA. Nephropathy was induced by an intravenous injection of Adriamycin. After Adriamycin injection, rats received lisinopril, prednisone, and ATRA treatment, respectively. Renal tissues were collected at Days 3, 7, 14, and 28. The distribution and the expression of messenger RNA and protein of nephrin, podocin, CD2AP, and alpha-actinin-4 were detected by indirect immunofluorescence, real-time polymerase chain reaction, and Western blotting, respectively. With the intervention of lisinopril, prednisone, and ATRA, changes in the expression of nephrin, podocin, and CD2AP were diverse, which was different from that detected in ADR rats. After lisinopril and prednisone intervention, podocin exhibited prominent earlier changes compared with those of nephrin and CD2AP, whereas CD2AP showed more prominent changes after ATRA intervention. There was no change in the expression of alpha-actinin-4 molecule. In summary, we conclude that the antiproteinuric effects of lisinopril, prednisone, and ATRA were achieved by changes in the expression and distribution of the important podocyte molecules nephrin, podocin, CD2AP, and alpha-actinin-4. The pattern in the change of podocyte molecules after lisinopril and prednisone intervention was similar, but the pattern in the change of podocyte molecules after ATRA intervention was different from that of lisinopril or prednisone intervention.
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PMID:Diversities of podocyte molecular changes induced by different antiproteinuria drugs. 1663 7

CD2AP, alpha-actinin-4 and podocalyxin are thought to play an important role in the structure and function of glomerular podocytes, therefore we intended to evaluate quantitatively, using computer image analysis system, the immunoexpression of these proteins in renal biopsy specimens in glomerulopathies presented with nephrotic syndrome: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and nephropathy IgA (IgAN). As a control 10 biopsy specimens of the kidneys removed because of trauma were used. In normal kidneys CD2AP, alpha-actinin-4, and podocalyxin showed intense staining in podocytes along the capillary walls of the glomeruli. The intensity of immunoexpression of CD2AP and alpha-actinin-4 in renal tissue in patients with MCD, FSGS, and IgAN was similar to normal controls, but the distribution of these proteins was more granular in glomeruli of diseased kidney. The immunostaining of podocalyxin was weaker in podocytes in patients with FSGS as compared with normal glomeruli. The immunostaining of podocalyxin was not significantly altered in MCD and IgAN. The immunostaining of CD2AP and alpha-actinin-4 did not correlate with the intensity of proteinuria in patients with MCD, FSGS and IgAN, whilst in FSGS patients the significant correlation was found between the glomerular immunostaining of podocalyxin and proteinuria. In conclusion, revealed in our study diminished immunoexpression of podocalyxin and significant correlation with the level of proteinuria in FSGS patients suggests a possible role of this sialoprotein in the alteration of the glomerular filtration barrier in this disease.
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PMID:Immunoexpression of podocyte-associated proteins in acquired human glomerulopathies with nephrotic syndrome. 1673 78

Nephrotic syndrome (NS) is one of the most frequent syndromes characterized namely by heavy proteinuria. Majority of NS occurs as a sporadic form, the incidence of familial cases is from 3 to 5%. Seven genes have been recognized till present, which mutations are responsible for severe forms of NS: NPHS1, NPHS2, ACTN4, CD2AP and WT1, TRPC6, LAMB2. Proteins encoded by these genes (nephrin, podocin, alpha-actinin-4, an adapter protein anchoring CD2 and others) influence the function of the podocytes. In cases of mutation in NPHS1 gene, causing congenital nephrotic syndrome of the Finnish type (CNF), resistance to steroid therapy occurs regularly and recurrence of proteinuria after renal transplantation is about 20-25%. Mutations in NPHS2 gene lead to autosomal recessive steroid resistant nephrotic syndrome (histologically focal segmental glomerulosclerosis). It was concluded that patients with steroid resistant nephrotic syndrome (SRNS) with homozygous or compound heterozygous mutations in NPHS2 have reduced risk for recurrence of focal segmental glomerulosclerosis (FSGS) in renal transplant (only 8% in comparison with 35% in patients without mutation in NPHS2). A functional polymorphism of NPHS2 gene--R229Q was associated with a late-onset nephrotic syndrome and also with an increased risk of microalbuminuria in the general population. The R229Q variant encodes a protein with lower affinity for binding nephrin. This polymorphism appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. There are also 3 genetic loci connected with autosomal dominant forms of FSGS: ACTN4, TRPC6 and CD2AP (found only in the mice models). These forms of FSGS differ from the recessive form by later-onset and more slowly progressive course of the disease; these mutations seem to be responsible for only a fraction of the autosomal dominant pattern of FSGS.
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PMID:Genetic basis of nephrotic syndrome--review. 1675 99

Primary defects in either podocytes or the glomerular basement membrane (GBM) cause proteinuria, a fact that complicates defining the barrier to albumin. Laminin beta2 (LAMB2) is a GBM component required for proper functioning of the glomerular filtration barrier. To investigate the GBM's role in glomerular filtration, we characterized GBM and overlying podocyte architecture in relation to development and progression of proteinuria in Lamb2-/- mice, which model Pierson syndrome, a rare congenital nephrotic syndrome. We found ectopic deposition of several laminins and mislocalization of anionic sites in the GBM, which together suggest that the Lamb2-/- GBM is severely disorganized, although it is ultrastructurally intact. Importantly, albuminuria was detectable shortly after birth and preceded podocyte foot process effacement and loss of slit diaphragms by at least 7 days. Expression and localization of slit diaphragm and foot process-associated proteins appeared normal at early stages. GBM permeability to the electron-dense tracer ferritin was dramatically elevated in Lamb2-/- mice, even before widespread foot process effacement. Increased ferritin permeability was not observed in nephrotic CD2-associated protein-null (Cd2ap-/-) mice, which have a primary podocyte defect. Together these data show that the GBM serves as a barrier to protein in vivo and that the glomerular slit diaphragm alone is not sufficient to prevent the passage of albumin into the urinary space.
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PMID:Proteinuria precedes podocyte abnormalities inLamb2-/- mice, implicating the glomerular basement membrane as an albumin barrier. 1688 57

Although the role of glomerular basement membrane has been emphasised as the barrier for retaining plasma proteins in the past three decades, some recent studies have demonstrated that the slit diaphragm of the glomerular epithelial cell (podocyte) is the structure likely to be the barrier in the glomerular capillary wall. Nephrin and podocin were identified as gene products mutated in Finnish-type congenital nephrotic syndrome and autosomal recessive steroid-resistant nephrotic syndrome, respectively. Nephrin s located at the outer leaflet of plasma membranes of the slit diaphragm. Podocin is reported to have an interaction with nephrin. The anti-nephrin antibody is capable of inducing massive proteinuria, which indicates that nephrin is a key functional molecule in the slit diaphragm. The expression of nephrin and podocin was reduced in glomeruli of minimal change nephrotic syndrome, which suggested that the altered expression of these molecules contributes to the development of proteinuria also in acquired diseases. Some recent studies demonstrated that CD2-associated protein (CD2AP) is also a functional molecule in the slit diaphragm, and its expression is altered in membranous nephropathy. These observations suggested that alteration of the molecular arrangement in the slit diaphragm is involved in the development of proteinuria in several kinds of glomerular diseases.
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PMID:Role of podocyte slit diaphragm as a filtration barrier. 1688 64

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.
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PMID:Expression profile of nephrin, podocin, and CD2AP in Chinese children with MCNS and IgA nephropathy. 1694 Nov 46

Synaptic vesicle protein 2B (SV2B) was identified by the subtraction hybridization technique as a molecule of which mRNA expression was decreased in puromycin aminonucleoside (PAN) nephropathy by glomerular cDNA subtraction assay. The expression of SV2B was detected in glomerular lysate with Western blot analysis. Dual-labeling immunofluorescence studies with glomerular cell markers demonstrated that SV2B is expressed in glomerular visceral epithelial cells (podocytes). The expression of SV2B is detected also in cultured podocyte and in human kidney section as podocytic pattern. The decrease of SV2B mRNA was already detected before the onset of proteinuria in PAN nephropathy. The mRNA expression of SV2B clearly is altered not only in PAN nephropathy but also in another proteinuric state that is caused by an antibody against nephrin, a functional molecule of the slit diaphragm. The decreased intensity in SV2B staining was already detected before the peak of proteinuria in both models with immunofluorescence study. A reduced amount of SV2B was detected in both models also with Western blot analysis. CD2AP, another functional molecule of the slit diaphragm, was observed in cytoplasm, including the processes area of the cultured podocyte, and when the podocyte was treated with small interfering RNA for SV2B, CD2AP staining at the process area was not detected. These results suggest that SV2B is a functional molecule of podocyte, and SV2B may play a role in the expression and proper localization of CD2AP.
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PMID:Synaptic vesicle protein 2B is expressed in podocyte, and its expression is altered in proteinuric glomeruli. 1694 7

Familial and genetic forms of focal segmental glomerulosclerosis (FSGS) are associated with six different mutations in genes affecting the podocyte (NPHS2, ACTN4, CD2AP, WT1, TRPC6, and PLCE1). Immunosuppressive agents are often unsuccessful in treating this condition. Data regarding the efficacy of renoprotection through blockage of the renin-angiotensin axis is lacking. We describe three children from two different families with familial FSGS in whom partial to complete remission of proteinuria was attained through early blockade of the renin-angiotensin axis. In addition, there was no deterioration of renal function. We speculate that presymptomatic patients with normal renal function who have genetic or familial FSGS may benefit from early blockade of the renin-angiotensin axis and that this may also prevent progressive renal disease.
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PMID:Renin-angiotensin axis blockade reduces proteinuria in presymptomatic patients with familial FSGS. 1753 Feb 96


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