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)

In diabetic nephropathy, connective tissue growth factor (CTGF) is upregulated and bone morphogenetic protein 7 (BMP-7) is downregulated. CTGF is known to inhibit BMP-4, but similar cross-talk between BMP-7 and CTGF has not been studied. In this study, it was hypothesized that CTGF acts as an inhibitor of BMP-7 signaling activity in diabetic nephropathy. Compared with diabetic wild-type CTGF(+/+) mice, diabetic CTGF(+/-) mice had approximately 50% lower CTGF mRNA and protein, less severe albuminuria, no thickening of the glomerular basement membrane, and preserved matrix metalloproteinase (MMP) activity. Although the amount of BMP-7 mRNA was similar in the kidneys of diabetic CTGF(+/+) and CTGF(+/-) mice, phosphorylation of the BMP signal transduction protein Smad1/5 and expression of the BMP target gene Id1 were lower in diabetic CTGF(+/+) mice. Moreover, renal Id1 mRNA expression correlated with albuminuria (R = -0.86) and MMP activity (R = 0.76). In normoglycemic mice, intraperitoneal injection of CTGF led to a decrease of pSmad1/5 in the renal cortex. In cultured renal glomerular and tubulointerstitial cells, CTGF diminished BMP-7 signaling activity, evidenced by lower levels of pSmad1/5, Id1 mRNA, and BMP-responsive element-luciferase activity. Co-immunoprecipitation, solid-phase binding assay, and surface plasmon resonance analysis showed that CTGF binds BMP-7 with high affinity (Kd approximately 14 nM). In conclusion, upregulation of CTGF inhibits BMP-7 signal transduction in the diabetic kidney and contributes to altered gene transcription, reduced MMP activity, glomerular basement membrane thickening, and albuminuria, all of which are hallmarks of diabetic nephropathy.
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PMID:CTGF inhibits BMP-7 signaling in diabetic nephropathy. 1863 43

DN (diabetic nephropathy) is the leading cause of end-stage renal disease worldwide and develops in 25-40% of patients with Type 1 or Type 2 diabetes mellitus. Elevated blood glucose over long periods together with glomerular hypertension leads to progressive glomerulosclerosis and tubulointerstitial fibrosis in susceptible individuals. Central to the pathology of DN are cytokines and growth factors such as TGF-beta (transforming growth factor beta) superfamily members, including BMPs (bone morphogenetic protein) and TGF-beta1, which play key roles in fibrogenic responses of the kidney, including podocyte loss, mesangial cell hypertrophy, matrix accumulation and tubulointerstitial fibrosis. Many of these responses can be mimicked in in vitro models of cells cultured in high glucose. We have applied differential gene expression technologies to identify novel genes expressed in in vitro and in vivo models of DN and, importantly, in human renal tissue. By mining these datasets and probing the regulation of expression and actions of specific molecules, we have identified novel roles for molecules such as Gremlin, IHG-1 (induced in high glucose-1) and CTGF (connective tissue growth factor) in DN and potential regulators of their bioactions.
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PMID:Regulation and consequences of differential gene expression in diabetic kidney disease. 1879 65

The onset of diabetic nephropathy is characterised by a rise in albumin excretion rate (AER) and/or a transient rise in glomerular filtration rate (GFR) (hyperfiltration). Without intervention AER increases exponentially and there is a linear decrease in GFR after onset of overt nephropathy. In overt nephropathy, AER is a predictor of decline in GFR and the early AER response to antihypertensive therapy correlates with long-term decline in GFR. AER can be measured by immunoassay or by other techniques including HPLC. However, HPLC assays result in higher levels of AER in normal subjects compared with immunoassayable AER. Recent data suggest that there are distinct albuminuric and non-albuminuric pathways to renal impairment in type 1 and type 2 diabetes. In type 2 diabetes, the non-albuminuric pathway may explain a decline in GFR to <60 ml/min/1.73 m(2) in approximately one in four subjects after accounting for the use of renin angiotensin system inhibitors. In established nephropathy (chronic kidney disease (CKD) stages 3 and 4), plasma cystatin C based estimates of GFR are marginally superior to creatinine based estimates. However, cystatin C clearly outperforms creatinine based estimates of GFR decline at GFR levels >60 ml/min/1.73 m(2) (CKD stages 1 and 2). Other potential markers of progression of diabetic nephropathy include transforming growth factor beta (TGFbeta) and connective tissue growth factor (CTGF). However, long-term studies are needed to define their roles as markers of progression. Diabetic nephropathy is likely to be more susceptible to intervention at an early stage and accurate estimation of GFR is already possible with cystatin C. However, improved formulas for estimating GFR based on using creatinine or other markers are still required, because this may still provide the most cost effective approach applicable to existing clinical practice.
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PMID:New and old markers of progression of diabetic nephropathy. 1893 92

Pathological remodeling characterized by extracellular matrix (ECM) accumulation contributes to diabetic nephropathy (DN). This study evaluated the effects of Ginkgo biloba extract (GbE) on the metabolism of the ECM in rat mesangial cells cultured in hyperglycemic conditions. The cultured mesangial cells in high glucose conditions were allotted into six groups: normal control group, high glucose group, low concentration of GbE group, moderate concentration of GbE group, high concentration of GbE group, and captopril group. In the presence of high glucose, the levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and extracellular matrix metalloproteinase inducer (EMMPRIN) were decreased significantly, and the levels of tissue inhibitor of metalloproteinase-2 (TIMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) were increased significantly. These changes were reversed by GbE. GbE lowered the levels of transforming growth factor-beta(1) (TGF-beta(1)), insulin-like growth factor-1 (IGF-1) and connective tissue growth factor (CTGF) of the high glucose group. Furthermore, GbE also decreased the expressions of collagen IV and laminin of the high glucose group. In summary, the results suggest that GbE postpones the extracellular matrix accumulation by inhibiting the synthesis of ECM and promoting the degradation of ECM, and therefore, is a potential drug for the prevention and treatment of DN.
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PMID:Ginkgo biloba extract prevents glucose-induced accumulation of ECM in rat mesangial cells. 1900 45

Connective tissue growth factor (CTGF/CCN2) is a member of the CCN family of matricellular proteins. Its expression is induced by a number of factors including TGF-beta. It has been associated with fibrosis in various tissues including the kidney. Diabetic nephropathy (DN) develops in about 30% of patients with diabetes and is characterized by thickening of renal basement membranes, fibrosis in the glomerulus (glomerulosclerosis), tubular atrophy and interstitial fibrosis, all of which compromise kidney function. This review examines changes in CTGF expression in the kidney in DN, the effects they have on glomerular mesangial and podocyte cells and the tubulointerstitium, and how these contribute to driving fibrotic changes in the disease. CTGF can bind to several other growth factors modifying their function. CTGF is also able to interact with receptors on cells, including integrins, tyrosine receptor kinase A (TrkA), low density lipoprotein receptor-related protein (LRP) and heparan sulphate proteoglycans. These interactions, the intracellular signalling pathways they activate, and the cellular responses evoked are reviewed. CTGF also induces the expression of chemokines which themselves have pharmacological actions on cells. CTGF may prompt some responses by acting through several different mechanisms, possibly simultaneously. For example, CTGF is often described as an effector of TGF-beta. It can promote TGF-beta signalling by binding directly to the growth factor, promoting its interaction with the TGF-beta receptor; by triggering intracellular signalling on binding the TrkA receptor, which leads to the transcriptional repression of Smad7, an inhibitor of the TGF-beta signalling pathway; and by binding to BMP-7 whose own signalling pathway opposing TGF-beta is inhibited, leading to enhanced TGF-beta signalling.
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PMID:Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? 1921 81

Diabetic nephropathy is characterized by decreased expression of bone morphogenetic protein-7 (BMP-7) and decreased podocyte number and differentiation. Extracellular antagonists such as connective tissue growth factor (CTGF; CCN-2) and sclerostin domain-containing-1 (SOSTDC1; USAG-1) are important determinants of BMP signaling activity in glomeruli. We studied BMP signaling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF(+/+) and CTGF(+/-) mice. BMP signaling activity was visualized by phosphorylated Smad1, -5, and -8 (pSmad1/5/8) immunostaining, and related to expression of CTGF, SOSTDC1, and the podocyte differentiation markers WT1, synaptopodin, and nephrin. In control and diabetic glomeruli, pSmad1/5/8 was mainly localized in podocytes, but both number of positive cells and staining intensity were decreased in diabetes. Nephrin and synaptopodin were decreased in diabetic glomeruli. Decrease of pSmad1/5/8 was only partially explained by decrease in podocyte number. SOSTDC1 and CTGF were expressed exclusively in podocytes. In diabetic glomeruli, SOSTDC1 decreased in parallel with podocyte number, whereas CTGF was strongly increased. In diabetic CTGF(+/-) mice, pSmad1/5/8 was preserved, compared with diabetic CTGF(+/+) mice. In conclusion, in human diabetic nephropathy, BMP signaling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1.
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PMID:BMP signaling and podocyte markers are decreased in human diabetic nephropathy in association with CTGF overexpression. 1925 50

Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p<0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p<0.01 and p<0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R=0.49, p<0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R=0.61, p<0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease.
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PMID:Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy. 1940 9

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and one of the leading causes of death among patients with diabetes. DN is characterized by excessive amassing of extracellular matrix with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. The high intracellular glucose environment due to an increased cellular uptake of glucose activates several pathways related to the production of advanced glycation endproducts, cytokines, chemokines, growth factors, reactive oxidative species, which are all final mediators of renal damage in human and experimental diabetes. Several growth factors have been implicated in the pathogenesis of DN, through complex intra-renal systems. Transforming growth factor beta, connective tissue growth factor, vascular endothelial growth factor, growth hormone and insulin-like growth factors are among those best known and investigated. There are also data, even though limited, on the involvement of other two growth factors, epidermal growth factor and platelet derived growth factor, in the pathogenesis of DN. These growth factors, which are generally expressed in the normal kidney and whose levels increase in relation to diabetes, have been implicated in the control of renal matrix composition, cell hypertrophy, proliferation and survival, modulation of cells of the immune system, and enzymes involved in glucose metabolism. The development of specific inhibitors of growth factors has provided further evidence for the involvement of growth factors in the development and progression of DN and further studies might help in developing new potential therapeutical interventions.
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PMID:Role of growth factors in diabetic kidney disease. 1945 24

Chronic kidney fibrosis is the unifying pathological feature of diverse renal disease leading to a progressive decline in renal function and eventually end-stage kidney failure. Many growth factors are able to induce an imbalance of extracellular matrix production and degradation, leading to excessive matrix and fibrosis in both glomeruli and in the tubulointerstitium. Over the last decade the role of connective tissue growth factor (CTGF) in renal fibrosis has been intensively studied. CTGF participates in cell proliferation, migration, and differentiation and mediates profibrotic activity by acting either directly, or as a co-factor for TGF beta 1, which is well characterised as a key cytokine mediating both the induction and promotion of fibrogenesis. CTGF also has the potential to modulate factors such as VEGF and bone morphogenic proteins, which are integral to both the development and repair process inherent in renal fibrogenesis. This review focuses on the role of CTGF in renal fibrosis and specifically its role in inducing fibrosis by factors integrally involved in the development of diabetic nephropathy, namely high glucose, angiotensin II, TGF beta 1 and AGEs.
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PMID:CTGF and chronic kidney fibrosis. 1948 89

Astilbin, a flavonoid compound, was isolated from the rhizome of Smilax glabra Roxb. This study was conducted to investigate the efficacy of astilbin on experimental diabetic nephropathy (DN) in vivo and in vitro and its possible mechanisms. Astilbin was added in high glucose stimulated HK-2 cells, streptozotocin-induced experimental DN, randomized to receive intragastric ( I. G.) astilbin to observe its anti-renal lesion effect. Results showed that astilbin inhibited high glucose stimulated HK-2 cell production of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in vitro, especially CTGF; analogic results was also found in vivo. I. G. of astilbin 2.5 mg/kg or 5 mg/kg significantly ameliorated renal function, reduced kidney index, while it increased body weight and survival time in animals. In addition there was no significant difference in blood glucose level between the STZ-treated group and the astilbin groups. Furthermore, astilbin ameliorated the pathological progress of renal morphology. Astilbin can exert an early renal protective role to DN, inhibit production of TGF-beta1 and especially of CTGF. We suggest that astilbin inhibition of CTGF may be a potential target in DN therapy. This work provides the first evidence for astilbin as a new candidate of DN therapeutic medicine.
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PMID:Effect of astilbin on experimental diabetic nephropathy in vivo and in vitro. 1964 10


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