Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy (DN), a major cause of ESRD, is undoubtedly multifactorial and is caused by environmental and genetic factors. To identify a genetic basis for DN susceptibility, we are collecting multiplex DN families in the Caucasian (CA) and African-American (AA) populations for whole genome scanning and candidate gene analysis. A candidate gene search of diabetic sibs discordantly affected, concordantly affected and concordantly unaffected for DN was performed with microsatellite markers in genomic regions suspected to harbor nephropathy susceptibility loci. Regions examined were at human chromosome 10p,10q (orthologous to the rat renal susceptibility Rf-1 locus), and at NPHS1 (nephrin), CD2AP, Wilms tumor (WT1), and NPHS2 (podocin) loci. Linkage analyses were conducted using model-free methods (SIBPAL, S.A.G.E.) for AA, CA, and the combined sample. Allele frequencies and the identity by descent sharing were estimated separately for AA and CA, and race was included as a covariate in the final linkage analysis. To date, we have collected 212 sib pairs from 46 CA and 50 AA families. The average age of diabetes onset was 46.8 yr versus 36.2 yr for CA and 39.5 yr versus 40.2 yr for AA, in males versus females respectively. Genotyping data were available for 106 sib pairs (43 CA, 63 AA) from 27 CA (44% male probands) and 38 AA families (43% male probands). Average AA and CA sibship size was 2.73. Singlepoint and multipoint linkage analyses indicate that marker D10S1654 on chromosome 10p is potentially linked to DN (CA only multipoint P = 4 x 10(-3)). Interestingly, the majority of the linkage evidence derives from the CA sib pairs. We are now adding sib pairs and increasing marker density on chromosome 10. We have excluded linkage with candidate regions for nephrin, CD2AP, WT1, and podocin in this sample. In conjunction with previous reports, our data support evidence for a DN susceptibility locus on chromosome 10.
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PMID:Linkage analysis of candidate loci for end-stage renal disease due to diabetic nephropathy. 1281 28

Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied, including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r = -0.443, P < 0.05), whereas it was positively correlated with podoplanin mRNA levels (r = 0.468, P < 0.05) and proteinuria (r = 0.585, P = 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.
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PMID:Expression of podocyte-associated molecules in acquired human kidney diseases. 1287 60

Molecular mechanisms governing the loss of glomerular membrane perm selectivity during progression of proteinuric kidney diseases are so far poorly defined. Discovery of the proteins of the podocyte slit diaphragm, including the nephrin-CD2AP-podocin complex, has represented a major breakthrough in understanding the crucial role of the glomerular epithelial layer in the pathogenesis of proteinuria in human congenital disorders. A number of studies have tried to address the role of nephrin in acquired proteinuric disorders with conflicting results. In human diabetic nephropathy a defect of nephrin gene and protein expression has been consistently reported, which translates in profound changes of filtration slit ultrastructural architecture. The exclusive effect of angiotensin II inhibitors of restoring deficient nephrin expression in proteinuric diseases underlines a close interaction between angiotensin II and podocyte proteins and indicates a fresh way to look at the renoprotective properties of these molecules.
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PMID:Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte dysfunction and slit diaphragm protein rearrangement. 1501 25

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of (125)I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.
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PMID:Altered transcapillary escape of albumin and microalbuminuria reflects two different pathogenetic mechanisms. 1561 33

We previously demonstrated the anti-inflammatory effects and renal tissue protection in response to adenosine A(2A)-receptor (A(2A)R) activation in acute renal injury. We sought to extend these studies and determine the efficacy of A(2A)R agonists in a chronic model of renal injury. We hypothesized that A(2A) agonists mediate renal tissue protection in diabetic nephropathy by reducing glomerular inflammation. Diabetes was induced with single intravenous injection of streptozotocin in Sprague-Dawley rats (50 mg/kg). Increases in urinary albumin excretion (UAE) and plasma creatinine at week 6 in the diabetes group (26- and 6-fold over control, respectively) were markedly reduced by continuous subcutaneous administration of ATL146e (10 ng x kg(-1) x min(-1)), a selective A(2A) agonist. The increase in UAE in the diabetes group was associated with a significant reduction in the expression of slit diaphragm-associated molecules compared with control (nephrin; P < 0.05 and podocin; P < 0.005) that was reversed by ATL146e treatment. Diabetes led to an increase in urinary excretion of monocyte chemoattractant protein-1 (705% of control), TNF-alpha (1,586% of control), IFN-gamma (298% of control), kidney fibronectin mRNA (457% of control), and glomerular infiltration of macrophages (764% of control), effects significantly reduced by ATL146e treatment. Mesangial expansion and basement membrane thickness were reduced with ATL146e. To further confirm the selectivity of ATL146e, we used wild-type (WT) or A(2A)knockout (A(2A)-KO) mice. Four weeks after diabetes, UAE increased significantly in both WT and A(2A)-KO diabetic mice (3.0- and 3.3-fold over control). A(2A) agonist treatment blocked the increase in UAE in WT diabetic mice (P < 0.001), whereas it had no effect on the A(2A)-KO diabetic mice. These results demonstrate that chronic A(2A)R activation in diabetic rats 1) ameliorates histological and functional changes in kidneys induced by diabetes and 2) causes reduced inflammation associated with diabetic nephropathy.
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PMID:Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy. 1633 31

Albuminuria in diabetic nephropathy is due to endothelial dysfunction, a loss of negative charges in the basement membrane, and changes a of the slit-membrane diaphragm composition. We have recently shown that protein kinase C alpha (PKCalpha)-deficient mice are protected against the development of albuminuria under diabetic conditions. We here tested the hypothesis that PKCalpha mediates the hyperglycemia-induced downregulation of the slit-diaphragm protein nephrin. After 8 weeks of streptozotocin (STZ)-induced hyperglycemia the expression of glomerular nephrin was significantly reduced. In contrast, other slit-diaphragm proteins such as podocin and CD2AP were unaltered in diabetic state. In PKCalpha-/- mice, hyperglycemia-induced downregulation of nephrin was prevented. Podocin and CD2AP remained unchanged. In addition, the nephrin messenger RNA expression was also reduced in hyperglycemic wild-type mice but remained unaltered in PKCalpha-/- mice. We postulate that the underlying mechanism of the hyperglycemia-induced regulation of various proteins of the glomerular filtration barrier is a PKCalpha-dependent regulation of the Wilms' Tumor Suppressor (WT1) which previously has been shown to act as a direct transcription factor on the nephrin promoter. Our data suggest that PKCalpha activation may be an important intracellular signaling pathway in the regulation of nephrin expression and glomerular albumin permeability in the diabetic state.
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PMID:Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo. 1695 3

Micro-vascular and renal complications in diabetic patients are a considerable clinical challenge. In a previous study, we found a significant decrease in vascular endothelial growth factor A (VEGF-A) mRNA levels in glomeruli from patients with diabetic nephropathy (DN). We now set out to investigate the relationship between reduced VEGF-A and connective tissue growth factor (CTGF) expression levels, the number of podocytes, and the extent of interstitial fibrosis. Laser capture microdissection was applied to obtain glomerular RNA from 28 patients with DN and 22 controls. mRNA levels of VEGF-A, CTGF, nephrin, podocin, and Wilms tumor1 (WT1) were measured using real-time polymerase chain reaction. Protein expression was evaluated using immuno-stainings for VEGF-A and CTGF, as well as markers for podocytes (WT1) and endothelial cells (CD31). We found a significant decrease in glomerular mRNA levels for VEGF-A (2.5 times), CTGF (1.6), nephrin (2.8), podocin (3.3), and WT1 (1.7) in patients with DN. There was a significant correlation between expression of podocyte markers and VEGF-A mRNA levels, and an inverse correlation between podocin message and the extent of interstitial fibrosis. CD31-positive area was significantly decreased (3.2 times) in patients with DN. Reduction of angiogenic factors correlated with the extent of interstitial fibrosis. This downregulation was related to a reduction of podocytes in DN. The results may suggest that downregulation of VEGF-A and CTGF in DN is a result of podocyte loss.
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PMID:Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. 1726 76

Nonimmune glomerulopathies are an area of significant research. This review discusses the development of focal segmental glomerulosclerosis, with particular attention to the role of the podocyte in the initiation of glomerulosclerosis and the contribution to glomerulosclerosis from capillary hypertension and soluble factors such as transforming growth factor beta, platelet-derived growth factor, vascular endothelial growth factor, and angiotensin. The effects of these factors on endothelial and mesangial cells are also discussed. In addition, we review our current understanding of the slit diaphragm (a specialized cell junction found in the kidney), slit diaphragm-associated proteins (including nephrin, podocin, alpha-actinin-4, CD2-associated protein, and transient receptor potential channel 6), and the role of these proteins in glomerular disease. We also discuss the most recent research on the pathogenesis of collapsing glomerulosclerosis, human immunodeficiency virus associated nephropathy, Denys-Drash, diabetic nephropathy, Alport syndrome, and other diseases related to the interaction between the podocyte and the glomerular basement membrane.
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PMID:Pathogenesis of nonimmune glomerulopathies. 1803 19

Connective tissue growth factor (CTGF) is a potent inducer of extracellular matrix accumulation. In diabetic nephropathy, CTGF expression is markedly upregulated both in podocytes and mesangial cells, and this may play an important role in its pathogenesis. We established podocyte-specific CTGF-transgenic mice, which were indistinguishable at baseline from their wild-type littermates. Twelve weeks after streptozotocin-induced diabetes, these transgenic mice showed a more severe proteinuria, mesangial expansion, and a decrease in matrix metalloproteinase-2 activity compared to diabetic wild-type mice. Furthermore, diabetic transgenic mice exhibited less podocin expression and a decreased number of diffusely vacuolated podocytes compared to diabetic wild-type mice. Importantly, induction of diabetes in CTGF-transgenic mice resulted in a further elevation of endogenous CTGF mRNA expression and protein in the glomerular mesangium. Our findings suggest that overexpression of CTGF in podocytes is sufficient to exacerbate proteinuria and mesangial expansion through a functional impairment and loss of podocytes.
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PMID:Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. 1823 18

The globally increasing number of patients with end-stage renal disease urges the identification of molecular pathways involved in renal pathophysiology, to serve as targets for intervention. Moreover, the identification of genetic risk factors or protective genes can aid tailored therapy. Tools that can be used to identify genes involved in renal disease include gene expression arrays, linkage analysis and association studies. Arrays are a powerful and widely used approach to the analysis of gene transcription and protein expression, whereas linkage analysis and association studies link disease susceptibility to particular genetic regions. Animal models are available to pinpoint the disease-associated genes. Candidate genes so far identified in renal disease include those encoding the podocyte proteins nephrin and podocin, the transcription factor WT1, the calcium channel TRPC6 and the enzyme phospholipase C-epsilon-1 (in congenital nephrotic syndrome and focal segmental glomerulosclerosis), and carnosinase (in diabetic nephropathy). In addition, linkage studies have identified chromosomal regions implicated in systemic lupus erythematosus, diabetic nephropathy and familial IgA nephropathy. Future studies will elucidate the emerging role of epigenetic regulation of gene expression in renal disease.
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PMID:Primer: strategies for identifying genes involved in renal disease. 1836 21


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