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

Prevalence of diabetic nephropathy is increasing. Understanding of pathogenesis and clinical picture helps to manage this disease. Recent data of the research of this disease support that the renin-angiotensin system plays a pivotal role in the pathogenesis. Hyperglycaemia activates the renin-angiotensin system and induces transforming growth factor-beta expression. These both lead to glomerulosclerosis and tubulointerstitial fibrosis. Diabetic nephropathy develops earlier and progress faster in patients with DD or ID genotypes of angiotensin-I-converting-enzyme gene. Angiotensinogen and type 1 angiotensin-II-receptor gene mutations may be also predisposing factors for diabetic nephropathy. All these factors can be responsible for the hyperfiltration, albuminuria, salt sensitivity, and hypertension, which are characteristic features of diabetic nephropathy. According to these, one can suppose that inhibitors of the renin-angiotensin system are effective in the prevention and treatment of this disease. Evidence of clinical studies suggests that angiotensin-I-converting-enzyme inhibitors in type 1 diabetes can prevent overt nephropathy, decrease proteinuria, inhibit the loss of the glomerular filtration and decelerate progression. Angiotensin-II-receptor blockers exert the same effect in type 2 diabetic patients, and presumably angiotensin-I-converting-enzyme inhibitors have similar activity in this group of patients. That is why, in the case of intolerance of one class of drugs, the other should be substituted. Combination therapy of angiotensin-I-converting-enzyme inhibitors with angiotensin-II-receptor blockers can be the choice of treatment in the future.
 ...
PMID:[Role of the renin-angiotensin system in the pathogenesis, clinical picture and treatment of diabetic nephropathy]. 1272 86

Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor-beta (TGF-beta) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-beta and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-beta monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and saline, while CAT-192 was ineffective. The addition of either TGF-beta antibody to lisinopril normalized proteinuria. Consistent results were obtained for glomerulosclerosis and tubular damage, which were abrogated by the combined therapy. Interstitial volume expansion and infiltration of lymphocytes/macrophages were limited by 1D11 and lisinopril and further reduced by their combination. The increase of type III collagen in the renal interstitium was partially attenuated by 1D11 and lisinopril while normalized by their combination. It is concluded that anti-TGF-beta antibody when added to a background of chronic angiotensin-converting enzyme (ACE) inhibition fully arrests proteinuria and renal injury of overt diabetic nephropathy, providing a novel route to therapy and remission of disease for diabetic patients who do not respond to RAS inhibition.
 ...
PMID:Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. 1281 41

TGF-beta (transforming growth factor-beta) is implicated in the pathogenesis of diabetic nephropathy. We previously demonstrated that up-regulation of type II TGF-beta receptor (TbetaRII) induced by high glucose might contribute to distal tubular hypertrophy [Yang, Guh, Yang, Lai, Tsai, Hung, Chang and Chuang (1998) J. Am. Soc. Nephrol. 9, 182-193]. We have elucidated the mechanism by using cultured Madin-Darby canine kidney cells. Enhancer assay and electrophoretic-mobility-shift assay were used to estimate the involvement of transcription factors. Western blotting and an in vitro kinase assay were used to evaluate the level and activity of protein kinase. We showed that glucose (100-900 mg/dl) induced an increase in mRNA level and promoter activity of TbetaRII (note: 'mg/dl' are the units commonly used in diabetes studies). The promoter region -209 to -177 appeared to contribute to positive transactivation of TbetaRII promoter by comparing five TbetaRII-promoter-CAT (chloramphenicol acetyl-transferase) plasmids. Moreover, the transcription factor AP-1 (activator protein 1) was significantly activated and specifically binds to TbetaRII promoter (-209 to -177). More importantly, we found that atypical PKC iota might be pivotal for high glucose-induced increase in both AP-1 binding and TbetaRII promoter activity. First, high glucose induced cytosolic translocation, activation and autophosphorylation of PKC iota. Secondly, antisense PKC iota expression plasmids attenuated high-glucose-induced increase in AP-1 binding and TbetaRII promoter activity; moreover, sense PKC iota expression plasmids enhanced these instead. Finally, we showed that antisense PKC iota expression plasmids might partly attenuate a high-glucose/TGF-beta1-induced increase in fibronectin. We conclude that PKC iota might mediate high-glucose-induced increase in TbetaRII promoter activity. In addition, antisense PKC iota expression plasmid effectively suppressed up-regulation of TbetaRII and fibronectin in hyperglycaemic distal-tubule cells.
 ...
PMID:Regulation of type II transforming-growth-factor-beta receptors by protein kinase C iota. 1284 49

Advanced glycation end products (AGEs) are produced by the non-enzymatic glycation of proteins and lipids. AGE levels are pathologically elevated in a number of inflammatory diseases and in diabetes mellitus. There is evidence that AGEs, acting through the receptor for AGEs, contribute to diabetic complications. Nephropathy is a major complication of diabetes mellitus. However, the initiating molecular events that trigger diabetic renal disease are unknown. Renal mesangial cells produce excess extracellular matrix in response to treatment with transforming growth factor-beta, and excess mesangial cell matrix production, by impairing glomerular filtration, contributes to diabetic nephropathy. AGEs are known to trigger the autocrine production and release of transforming growth factor-beta. However, it is unclear how AGEs signal in mesangial cells. Here we show that treatment of mesangial cells with AGEs and with the receptor for AGEs agonist S100 triggers activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K) pathways. AGEs trigger the GTP loading of mesangial cell Ras, and AGE activation of ERK requires Ras. We observe that Ki-Ras, but not Ha-Ras, is the target of AGE action. Surprisingly, inhibition of PI3K blocks both ERK and Ki-Ras activation. We also observe that activation of ERK and the PI3K target kinase protein kinase-B is blocked with free radical scavengers, indicating a role for reactive oxygen species in AGE recruitment of PI3K. Thus, AGEs signal to Ki-Ras and ERK through reactive oxygen species-dependent activation of PI3K.
 ...
PMID:Phosphatidylinositol 3'-kinase-dependent activation of renal mesangial cell Ki-Ras and ERK by advanced glycation end products. 1287 51

Tubulointerstitial fibrosis is an important component in the development of diabetic nephropathy. Various renal cell types, including fibroblasts, contribute to the excessive matrix deposition in the kidney. Although transforming growth factor-beta (TGF-beta) has been thought to play a major role during fibrosis, other growth factors are also involved. Here we examined the effects of connective tissue growth factor (CTGF) and IGF-I on collagen type I and III production by human renal fibroblasts and their involvement in glucose-induced matrix accumulation. We have demonstrated that both CTGF and IGF-I expressions were increased in renal fibroblasts under hyperglycemic conditions, also in the absence of TGF-beta signaling. Although CTGF alone had no effect on collagen secretion, combined stimulation with IGF-I enhanced collagen accumulation. Furthermore, IGF-I also had a synergistic effect with glucose on the induction of collagens. Moreover, we observed a partial inhibition in glucose-induced collagen secretion with neutralizing anti-CTGF antibodies, thereby demonstrating for the first time the involvement of endogenous CTGF in glucose-induced effects in human renal fibroblasts. Therefore, the cooperation between CTGF and IGF-I might be involved in glucose-induced matrix accumulation in tubulointerstitial fibrosis and might contribute to the pathogenesis of diabetic nephropathy.
 ...
PMID:Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. 1463 59

The intent of this review is to focus on recent advances in the understanding of the factors responsible for the progressive pathologic features of diabetic kidney disease, with special attention to various growth factors and cytokines that appear to be important in this process. In addition, emphasis is centered on relatively early stages of the disease, because animal models have been most helpful to date in understanding this stage of the disease process. Although tubulointerstitial changes are of critical importance in the progression of diabetic nephropathy, especially in the evolution to end-stage renal disease, there is a general consensus that glomerular pathology occurs first. Therefore, attention is limited to factors that may be important in the development of early diabetic glomerulopathy, including transforming growth factor-beta (TGF-beta), insulin-like growth factor (IGF)-I, vascular endothelial growth factor (VEGF)-A, and connective tissue growth factor (CTGF).
 ...
PMID:Trophic factors and cytokines in early diabetic glomerulopathy. 1466 46

Prolonged exposure to hyperglycemia is now recognized as the most significant causal factor of diabetic complications. Excessive advanced glycation end products (AGEs) as a result of hyperglycemia in tissues or in the circulation may critically affect the progression of diabetic nephropathy. In diabetic nephropathy, glomerulosclerosis is a typical pathologic feature characterized by the increase of the extracellular matrix (ECM). We have reported previously that alpha1 type IV collagen (Col4) is one of the major components of ECM, which is up-regulated by AGEs, and that the overexpression of Col4 is transcriptionally regulated by an unknown transcription factor binding to the promoter. Here we identified this protein as Smad1 by yeast one-hybrid screening. Using chromatin immunoprecipitation and reporter assay, we observed that Smad1 directly regulated transcription for Col4 through the binding of Smad1 to the promoter of Col4. Smad1 was significantly induced along with Col4 in AGE-treated mesangial cells. Moreover, suppression of Smad1 by antisense morpholino resulted in a decrease of AGE-induced Col4 overproduction. To elucidate the interaction between transforming growth factor-beta and Smad1, we investigated whether activin receptor-liked kinase1 (ALK1) was involved in this regulation. AGE stimulation significantly increased the expression of the ALK1 mRNA in mesangial cells. We also demonstrated that Smad1 and ALK1 were highly expressed in human diabetic nephropathy. These results suggest that the modulation of Smad1 expression is responsible for the initiation and progression of diabetic nephropathy and that blocking Smad1 signaling may be beneficial in preventing diabetic nephropathy and other various diabetic complications.
 ...
PMID:Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. 1473 18

The effects of overexpression of Cu(2+)/Zn(2+) superoxide dismutase-1 (SOD-1) on indexes of renal injury were compared in 5-month-old nontransgenic (NTg) db/db mice and db/db mice hemizygous for the human SOD-1 transgene (SOD-Tg). Both diabetic groups exhibited similar hyperglycemia and weight gain. However, in NTg-db/db mice, albuminuria, glomerular accumulation of immunoreactive transforming growth factor-beta, collagen alpha1(IV), nitrotyrosine, and mesangial matrix were all significantly increased compared with either nondiabetic mice or SOD-Tg-db/db. SOD-1 activity and reduced glutathione levels were higher, whereas malondialdehyde content was lower, in the renal cortex of SOD-Tg-db/db compared with NTg-db/db mice, consistent with a renal antioxidant effect in the transgenic mice. Inulin clearance (C(IN)) and urinary excretion of guanosine 3',5'-cyclic monophosphate (U(cGMP)) were increased in SOD-Tg-db/db mice compared with corresponding values in nondiabetic mice or NTg-db/db mice. C(IN) and U(cGMP) were suppressed by Nomega-nitro-L-arginine methyl ester in SOD-Tg-db/db but not in NTg-db/db mice, implying nitric oxide (NO) dependence of these increases and enhanced renal NO bioactivity in SOD-Tg-db/db. Studies of NO-responsive cGMP in isolated glomeruli supported greater quenching of NO in glomeruli from NTg-db/db compared with SOD-Tg-db/db mice. Evidence of increased NO responsiveness and the suppression of glomerular nitrotyrosine may both reflect reduced NO-superoxide interaction in SOD-Tg-db/db mice. The results implicate superoxide in the pathogenesis of diabetic nephropathy.
 ...
PMID:Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. 1498 62

Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
 ...
PMID:Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. 1500 23

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are ligand-activated transcription factors that regulate cell growth, inflammation, lipid metabolism, and insulin sensitivity. PPAR-gamma in the human kidney has been described. However, the role of PPAR-gamma in proximal tubular cells with respect to cell growth and inflammation in diabetic nephropathy is largely unknown. We evaluated the effect of high (30 mM) D-glucose, thiazolidinedione pioglitazone (10 microM), and the selective PPAR-gamma agonist L-805645 (8 microM) on PPAR-gamma expression, growth, and inflammatory parameters in the proximal tubular model of HK-2 cells. PPAR-gamma was present in HK-2 cells and upregulated with 30 mM D-glucose to 177 +/- 31.2% of control (P < 0.05). PPAR-gamma activation was induced by pioglitazone to a similar level to that observed by exposure to high glucose but maximally induced by the selective agonist L-805645. However, L-805645 reduced cell viability in both 5 and 30 mM d-glucose to 73.8 +/- 3.1 and 77.6 +/- 1.4% of control (both P < 0.0001). In parallel, thymidine incorporation was reduced with L-805645 in both 5 and 30 mM D-glucose to 33.3 +/- 3.4 and 37.9 +/- 2.2%, respectively (both P < 0.0001). Flow cytometry demonstrated increased apoptosis and G(1) phase arrest in association with an increase in p21(cip1/waf1) in cells exposed to L-805645. Exposure to 30 mM D-glucose did not significantly change AP-1 promoter activity (89.0 +/- 5.5% of control); however, the addition of L-805645 significantly reduced it to 62.2 +/- 2.7% of control (P < 0.0001). Thirty nanomolar D-glucose induced transforming growth factor-beta(1) to 137.7 +/- 16.9% of control (P < 0.05), and L-805645 was able to suppress this to 68.7 +/- 5.7% of control (P < 0.01 vs. d-glucose). Exposure to 30 mM D-glucose reduced monocyte chemoattractant protein 1 levels to 78.6 +/- 7.1% (P < 0.05) of control, with the reduction more marked in the presence of either pioglitazone (P < 0.01) or L-805645 (P < 0.01). In summary, high glucose upregulates PPAR-gamma and when significantly induced demonstrates anti-proliferative and anti-inflammatory effects.
 ...
PMID:The effect of high glucose and PPAR-gamma agonists on PPAR-gamma expression and function in HK-2 cells. 1511 52


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