Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.
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PMID:Congenital nephrotic syndrome in mice lacking CD2-associated protein. 1057 88

The molecular nature of the glomerular slit diaphragm, the site of renal ultrafiltration, has until recently remained a mystery. However, the identification of the gene affected in congenital nephrotic syndrome has revealed the presence of a novel protein, possibly specific for the slit diaphragm. This protein, which has been termed nephrin, is a transmembrane protein that probably forms the main building block of an isoporous zipper-like slit diaphragm filter structure. Defects in nephrin lead to abnormal or absent slit diaphragm leading to massive proteinuria and renal failure. The discovery of nephrin sheds new light on the glomerular filtration barrier, provides new insight into the pathomechanisms of proteinuria, and even opens up possibilities for the development of novel therapies for this common and severe kidney complication.
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PMID:Discovery of the congenital nephrotic syndrome gene discloses the structure of the mysterious molecular sieve of the kidney. 1053 22

Podocytes are highly specialized cells that make up a major portion of the glomerular filtration barrier in the kidney. They are also believed to play a pivotal role in the progression of chronic renal disease due to diverse causes that include diabetes (3, 20, 24) and aging (1, 7). Despite the importance of podocytes for kidney function and disease, studies of this cell type have been hindered due to a lack of model systems. Recently, the gene responsible for congenital Finnish nephropathy was identified and named nephrin (13). Nephrin expression is restricted to slit diaphragms of podocytes (11, 30). Infants with congenital Finnish nephropathy develop massive proteinuria and subsequent kidney failure due to podocyte injury. We have identified a 1.25-kb DNA fragment from the human nephrin promoter and 5'-flanking region that is capable of directing podocyte-specific expression in transgenic mice; this represents the first glomerular-specific promoter to be identified. Use of this transgene will facilitate studies of the podocyte in vivo and allow the identification of transacting factors that are required for podocyte-specific expression.
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PMID:Identification and characterization of a glomerular-specific promoter from the human nephrin gene. 1109 20

CD2AP, an adapter protein containing multiple SH3 domains, plays a critical role in kidney function. Mice lacking CD2AP die soon after birth because of kidney failure. In the kidney, CD2AP is expressed in glomerular podocytes, which suggests that it may play a role in a specialized adhesion complex known as the slit diaphragm. One of the major components of the slit diaphragm is nephrin, a podocyte-specific protein. Here we demonstrate that CD2AP localizes to the slit diaphragm in podocytes using immunoelectron microscopy and that nephrin and CD2AP co-immunoprecipitate from a podocyte cell line. The specificity of this interaction was verified by mapping studies, which demonstrated that a novel domain at the C terminus of CD2AP interacts with the C-terminal portion of the nephrin cytoplasmic domain. These studies lend further support to the idea that CD2AP plays a role in the structural integrity of the slit diaphragm.
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PMID:CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C-terminal domain. 1173 79

Nephrotic syndrome is a clinical and laboratory syndrome caused by the increased permeability of the glomerular capillary wall for macromolecules. Nephrotic syndrome is a potentially life-threatening state and persistent nephrotic syndrome has a poor prognosis with a high risk of progression to end-stage renal failure and a high risk of cardiovascular complications due to severe hyperlipidemia. Pathogenesis of increased glomerular permeability in different glomerular diseases has not been fully elucidated. Recently, identification of the mutated genes for some podocyte proteins (nephrin, podocin, alpha-actinin-4) in rare familial forms of nephrotic syndrome shed has new light on the molecular mechanisms of glomerular permselectivity. Gradually it becomes apparent that sporadic mutations of podocyte proteins (e.g., podocin) may be present even in some patients with acquired nephrotic syndrome. Expression of other podocyte proteins may change during the course of experimental nephrotic syndrome, possibly as a response to podocyte damage resulting either in apoptosis or stimulation of proliferation and some form of repair, including glomerular sclerosis. Better understanding of these mechanisms could clearly also have therapeutic implications. Glomerular permeability factors are believed to play a role in some noninflammatory glomerular diseases, mainly minimal change disease and focal segmental glomerulosclerosis, but their molecular identification remains elusive, possibly due to the nonhomogeneous nature of the underlying diseases. As an example, focal segmental glomerulosclerosis possibly can be caused by the sporadic mutation of some genes for podocyte proteins, increased production of glomerular permeability factor (possibly by T lymphocytes), or the loss of inhibitors of glomerular permeability factors in nephrotic urine. Clearly the factors causing increased glomerular permeability and factors perpetuating glomerular sclerosis are not necessarily the same. Proteinuria does not seem to be only the consequence of glomerular damage, but it may possibly cause tubular damage and initiate interstitial fibrosis and thus contribute to the progression of chronic renal failure in proteinuric renal diseases. Recent insights into the mechanisms of tubular protein reabsorption may give new tools for preventing the progression of chronic renal disease. Cubilin inhibitors could potentially ameliorate tubular and interstitial damage in patients with heavy proteinuria refractory to treatment. Nephrotic hyperlipidemia is accompanied with increased risk of cardiovascular complications and should be treated in all patients with persistent nephrotic syndrome. The putative positive effect of hypolipidemic drugs (namely statins) on the cardiovascular risk and potentially also on the rate of progression of chronic renal failure remains to be demonstrated in prospective controlled studies. Recent progress in understanding podocyte biology in rare inherited glomerular diseases gives the chance to understand in the near future the molecular pathogenesis of increased glomerular permeability in the much more common acquired forms of nephrotic syndrome.
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PMID:Pathobiochemistry of nephrotic syndrome. 1261 8

Hereditary nephrotic syndrome is a heterogeneous disease, characterized by heavy proteinuria and renal failure. Mutations of NPHS1 or NPHS2, the genes encoding for nephrin and podocin, lead to early onset of heavy proteinuria, and rapid progression to end-stage renal disease, suggesting that both proteins are essential for the integrity of the glomerular filter. Podocin is a stomatin protein family member with a predicted hairpin-like structure localizing to the insertion site of the slit diaphragm of podocytes, the visceral glomerular epithelial cells of the kidney. Here we investigate the pathomechanisms of different disease-causing podocin mutations. We show that wild-type podocin is targeted to the plasma membrane, and forms homo-oligomers involving the carboxy and amino terminal cytoplasmic domains. The association of podocin with specialized lipid raft microdomains of the plasma membrane was a prerequisite for recruitment of nephrin into rafts. In contrast, disease-causing mutations of podocin (R138Q and R138X) failed to recruit nephrin into rafts either because these mutants were retained in the endoplasmic reticulum (R138Q), or because they failed to associate with rafts (R138X) despite their presence in the plasma membrane. None of the mutants did augment nephrin signaling, suggesting that lipid raft targeting facilitates nephrin signaling. Our findings demonstrate that the failure of mutant podocin to recruit nephrin into lipid rafts may be essential for the pathogenesis of NPHS2.
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PMID:Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. 1457 Jul 3

Podocytes are specialized epithelial cells covering the basement membrane of the glomerulus in the kidney. The molecular mechanisms underlying the role of podocytes in glomerular filtration are still largely unknown. We generated podocin-deficient (Nphs2-/-) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis. Nphs2-/- mice developed proteinuria during the antenatal period and died a few days after birth from renal failure caused by massive mesangial sclerosis. Electron microscopy revealed the extensive fusion of podocyte foot processes and the lack of a slit diaphragm in the remaining foot process junctions. Using real-time PCR and immunolabeling, we showed that the expression of other slit diaphragm components was modified in Nphs2-/- kidneys: the expression of the nephrin gene was downregulated, whereas that of the ZO1 and CD2AP genes appeared to be upregulated. Interestingly, the progression of the renal disease, as well as the presence or absence of renal vascular lesions, depends on the genetic background. Our data demonstrate the crucial role of podocin in the establishment of the glomerular filtration barrier and provide a suitable model for mapping and identifying modifier genes involved in glomerular diseases caused by podocyte injuries.
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PMID:Early glomerular filtration defect and severe renal disease in podocin-deficient mice. 1470 29

Diabetic nephropathy is the most common cause world-wide of renal failure requiring renal replacement therapy, most patients having type 2 rather than type 1 diabetes. Cardiovascular risk increases progressively as nephropathy develops. In addition to abnormalities in the glomerular endothelium and mesangium, recent data suggest that changes are also seen in the glomerular epithelial cell or podocyte. The foot processes of the podocyte broaden and efface and there is loss of podocyte specific proteins such as nephrin. Eventually there is loss of podocytes themselves. These changes may contribute to proteinuria. The development of nephropathy can be prevented by good glucose and blood pressure control. Once microalbuminuria or proteinuria are present, control of intraglomerular pressure, using inhibitors of the renin-angiotensin system, and control of systemic blood pressure are paramount, and can delay the need for renal replacement therapy by many years. Aggressive management of cardiovascular risk factors also slows the progression of nephropathy and prevents cardiovascular events.
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PMID:Recent advances in diabetic nephropathy. 1524 65

Proteinuria has been demonstrated to be not only a representative sign of renal lesion but also a risk factor for the progression to renal failure through its injurious effects on tubulointerstitium. The responsible gene for Finnish type congenital nephrotic syndrome was identified and its product was named 'nephrin' which is located on slit membrane between foot processes of glomerular epithelial cells and is considered to be concerned also in the induction of acquired renal lesions with proteinuria. The monoclonal antibody against rat nephrin can induce proteinuria. These facts suggest that the important role for final barrier against macromolecules is played by the slit membrane. Understanding the proteinuria mechanism at molecular level is expected to lead to the establishment of appropriate treatments. Nephrin is regarded as the most promising and attractive molecule for the development of new therapeutic strategy. Many nephrologists are now much interested in the intimate relationship between nephrin and angiotensin II.
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PMID:[Responsible genes for proteinuria and concept of the treatment for proteinuria]. 1550 Jan 21

Increasing number of diabetic patients develop different stages of renal failure. However, often an inappropriate parameter, the serum creatinine is measured as a marker of glomerular function. Calculated glomerular filtration rate or endogenous creatinine clearance are suggested to be used for the estimation of the glomerular function. Important structures preventing proteinuria in the kidney are glomerular basement membrane, podocytes and proximal tubular cells. In diabetes mellitus loss of nephrin of podocytes can play a role in the development of microalbuminuria, and podocyte desquamation may result in the progression to proteinuria. In diabetes mellitus there is an increased formation of advanced glycation endproducts (AGE), of which the only elimination organ is the kidney. The AGE induce proteinuria and atherosclerosis. Therefore, in diabetes mellitus a vicious circle develops due to proteinuria, nephron loss and accumulation of AGE, which play a role in the initiation and progression of diabetic nephropathy and atherosclerosis. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers having antiproteinuric effect may decrease the risk of diabetic nephropathy and atherosclerosis. Improvement of carbohydrate metabolism with a consequential decrease in the formation of AGE is an important contributor to the prevention and treatment of diabetic nephropathy and atherosclerosis.
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PMID:Prevention and treatment of diabetic nephropathy. 1595 73


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