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 kidney disease has been associated with the presence of lipid deposits, but the mechanisms for the lipid accumulation have not been fully determined. In the present study, we found that db/db mice on the FVB genetic background with loss-of-function mutation of the leptin receptor (FVB-Lepr(db) mice or FVBdb/db) develop severe diabetic nephropathy, including glomerulosclerosis, tubulointerstitial fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased renal mRNA abundance of transforming growth factor-beta, plasminogen activator inhibitor-1, and vascular endothelial growth factor. Electron microscopy demonstrates increases in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked increase in neutral lipid deposits in glomeruli and tubules by oil red O staining and biochemical analysis for cholesterol and triglycerides. We also detected a significant increase in the renal expression of adipocyte differentiation-related protein (adipophilin), a marker of cytoplasmic lipid droplets. We examined the expression of sterol regulatory element-binding protein (SREBP)-1 and -2, transcriptional factors that play an important role in the regulation of fatty acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear extracts from the kidneys of FVBdb/db mice, with increases in the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and cholesterol content. Our results indicate that in FVBdb/db mice, renal triglyceride and cholesterol accumulation is mediated by increased activity of SREBP-1 and -2. Based on our previous results with transgenic mice overexpressing SREBP-1 in the kidney, we propose that increased expression of SREBPs plays an important role in causing renal lipid accumulation, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria in mice with type 2 diabetes.
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PMID:Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. 1604 98

An increased oxidative stress may contribute to the development of diabetic nephropathy. We have recently reported that high glucose level stimulated superoxide production through protein kinase C (PKC)-dependent activation of NAD(P)H oxidase in cultured vascular cells. Here we show that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor (statin) attenuates both high glucose level-induced and angiotensin II (Ang II)-induced activation of p42/44 mitogen-activated kinase (MAP kinase) in cultured human mesangial cells through inhibition of NAD(P)H oxidase activity. The intracellular oxidative stress in cultured mesangial cells was evaluated by electron spin resonance (ESR) measurement. MAP kinase activity was evaluated by western blot analysis using anti phospho-specific MAP kinase antibody and anti-ERK-1 antibody. Exposure of the cells to high glucose level (450 mg/dl) for 72 hrs significantly increased MAP kinase activity as compared to normal glucose level (100 mg/dl). This increase was completely blocked by the treatment of pitavastatin (5x10(-7) M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium, 10(-5) M) in parallel with the attenuation of oxidative stress. Ang II-induced activation of MAP kinase was also completely blocked by pitavastatin as well as a diphenylene iodonium in parallel with the attenuation of oxidative stress. In conclusion, pitavastatin attenuated high glucose-induced and Ang II- induced MAP kinase activity in mesangial cells through inhibition of NAD(P)H oxidase. Thus, statins may have a potential as a therapeutic tool for early diabetic nephropathy.
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PMID:Statin attenuates high glucose-induced and angiotensin II-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells. 1678 30