Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Impaired heparan sulphate biosynthesis through diabetes-induced inhibition of glucosaminyl N-deacetylase may have a central role in the development of diabetic nephropathy, and genetic differences in the vulnerability of the N-deacetylase could influence the risk of developing nephropathy. We studied N-deacetylase activity in fibroblast cultures from Type 1 (insulin-dependent) diabetic patients with (n = 14) or without (n = 13) diabetic nephropathy, together with non-diabetic control subjects (n = 7). No difference in N-deacetylase activity was found (p = 0.13), and no inhibition of N-deacetylase was found in cultures grown at 25 mmol/l glucose. N-deacetylase activity was inversely correlated to growth rate (r = -0.59, p = 0.0008), and in patients with nephropathy a negative correlation between HbA1C and fibroblast N-deacetylase activity (r = -0.72, p = 0.012) was found. Cell-cycle analysis revealed an increased fraction of S-phase cells in patients with nephropathy (28%(21-52%)) compared to healthy control subjects (17% (9-24%)), p = 0.0008, but not between patients with and without nephropathy (latter group 26%(11-43%)), p = 0.43. Forskolin, an activator of protein kinase A, specifically decreased N-deacetylase activity, whereas activation of protein kinase C produced a combined reduction in N-deacetylase activity and total protein synthesis. In conclusion, no constitutive defects in N-deacetylase activity were found in fibroblasts from these patients. Further studies should consider possible associations between fibroblast characteristics and pre-biopsy environmental parameters related to cellular memory phenomena. Finally, activation of protein kinase A provides a potential general pathway for regulating N-deacetylase activity.
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PMID:Glucosaminyl N-deacetylase in cultured fibroblasts; comparison of patients with and without diabetic nephropathy, and identification of a possible mechanism for diabetes-induced N-deacetylase inhibition. 833 76

Hepatocyte growth factor (HGF) is a prospective agent for therapy against a variety of nephrologic disorders including diabetic nephropathy, although the precise mechanisms for the effect of HGF remain to be elucidated. We have previously shown that HGF protects rat mesangial cells (RMC) from high glucose (HG)-mediated oxidative stress. In the present study, we focused on the pathway by which HGF exerts its protective effect on RMC after oxidative stress induced by high glucose. We show that either agonist of PKA forskolin or antagonist of PKG Rp-8-pCPT-cGMPS partly attenuated the inhibitory role of HGF on HG-increased oxidative stress in RMC as evidenced by elevated reactive oxygen species and malondialdehyde levels and decreased glutathione level. Moreover, Rp-8-pCPT-cGMPS blocked HGF-increased glutamate-cysteine ligase catalytic subunit (GCLC) expression in HG-treated RMC through enhancement of USF binding to the negative regulatory region of the GCLC promoter. Forskolin depressed HGF-increased glucose-6-phosphate dehydrogenase (G6PD) activity and expression in RMC cultured in HG. Correspondingly, HGF counteracted the effect of HG on PKA and PKG activity. Thus, inhibition of PKA and activation of PKG are involved in the antioxidant role of HGF.
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PMID:HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA. 2046 58

The present study aimed to investigate the role of adenylyl cyclase activator in preventing diabetic nephropathy in rats. Renal function parameters, renal hypertrophy, lipid profile, markers of oxidative stress and free radical scavenging activities were assessed. Histopathology was performed to confirm Streptozotocin induced renal morphological changes in diabetic rats. Male Wistar rats were used in the present study to reduce the effect of estrogen. Rats were subjected to high fat diet (HFD) for two weeks followed by low dose of Streptozotocin (STZ) [35 mg/kg, i.p.] to develop experimental diabetic nephropathy in eight weeks. Two weeks treatment with low dose of Forskolin (10 mg/kg) reduced the level of diabetic nephropathy markers but results observed were not significant. Whereas, Forskolin intermediate dose (20 mg/kg) and high dose (30 mg/kg) treated rats significantly attenuated diabetes induced elevated renal function parameters and endogenous antioxidants enzymatic activities. High dose of Forskolin was found to be more effective in attenuating the renal structural and functional abnormalities. Forskolin prevented renal structural and functional abnormalities in diabetic rats. Histopathological evaluation revealed that Forskolin (20 mg/kg and 30 mg/kg) treated diabetic rats demonstrated reduced vacuolar degeneration of tubules and glomerulosclerosis. In the present study, Glibenclamide (0.6 mg/kg) and Atorvastatin (0.5 mg/kg) were used as standard drugs. Our results demonstrated synergistic effects, when high dose of Forskolin was co-administered with standard drugs. In conclusion, treatment with adenylyl cyclase activator, Forskolin in diabetic rats reduced the elevated serum glucose level, biomarkers of renal morphological dysfunction, renal hypertrophy, dyslipidaemia, oxidative stress and improved renal structure, function and enhanced level of endogenous antioxidants. Forskolin has a potential to prevent nephropathy without showing any effect on body weight in diabetic rats.
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PMID:Role of adenylyl cyclase activator in controlling experimental diabetic nephropathy in rats. 3051 57

Podocyte is the major target in proteinuric kidney disease such as diabetic nephropathy. The underlying molecular mechanisms by which high glucose (HG) results in podocyte damage remain unclear. This study investigated the regulatory role of Smad3, ezrin, and protein kinase A (PKA) in NADPH oxidase (Nox4) expression, reactive oxidative species (ROS) production, and apoptosis in HG-treated podocytes. Human podocyte cell line was cultured and differentiated, then treated with 30 mM HG. Apoptosis and intracellular ROS level was assessed using TUNEL and DCF assay, respectively. Expressions of Nox4, phospho-Smad3^Ser423/425, phospho-PKA^Thr197, and phospho-ezrin^Thr567 were evaluated using Western blotting. ELISA was used to quantify intracellular cAMP concentration and PKA activity. Knockdown assay was used to inhibit the expressions of Smad3, Nox4, and ezrin by lentiviral shRNA. In HG-treated podocytes, the level of phospho-Smad3^Ser423/425 and phospho-ezrin^Thr567 was increased significantly, which was accompanied by the reduction of cAMP and phospho-PKA^Thr197 HG-induced apoptosis was significantly prevented by the Smad3 inhibitor SIS3 or shRNA-Smad3. In podocytes expressing shRNA-ezrin or shRNA-Nox4, apoptosis was remarkably mitigated following HG treatment. HG-induced upregulation of phospho-ezrin^Thr567 and downregulation of phospho-PKA^Thr197 was significantly prevented by SIS3, shRNA-ezrin or shRNA-Smad3. Forskolin, a PKA activator, significantly inhibited HG-mediated upregulation of Nox4 expression, ROS generation, and apoptosis. Additionally, an increase in the ROS level was prohibited in HG-treated podocytes with the knockdown of Nox4, Smad3, or ezrin. Taken together, our findings provided evidence that Smad3-mediated ezrin activation upregulates Nox4 expression and ROS production, by suppressing PKA activity, which may at least in part contribute to HG-induced podocyte apoptosis.
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PMID:High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway. 3304 39

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