Oxidized LDL stimulates the expression of TGF-β and fibronectin in human glomerular epithelial cells

Ding, Guohua; Goor, Harry van; Ricardo, Sharon D.; Orlowski, Janis M.; Diamond, Jonathan R.

doi:10.1038/ki.1997.18

Cited by 83 publications

(48 citation statements)

References 36 publications

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“…Moreover, Ox-LDL also promotes fibrosis by stimulating synthesis and expression of TGF-␤. 35 The redox-sensitive TGF-␤ regulates many fundamental biological processes and is a key mediator in chronic kidney disease. 36 We observed previously in early atherosclerosis increased tubular and glomerular TGF-␤ expression, 8 which could be manipulated by pharmacological intervention.…”

Section: Discussionmentioning

confidence: 99%

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

et al. 2005

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Abstract-Dyslipidemia often accompanies and accelerates renal disease, partly by promoting fibrosis. However, the mechanisms mediating this effect are unclear. We hypothesized that hypercholesterolemia modulates several interlinked pathways that promote deposition and blunt degradation of extracellular matrix, and that these could be manipulated by reversal of hypercholesterolemia. Fourteen pigs were fed a 16-week 2% high-cholesterol diet (HC-HC; nϭ7) or normal diet (nϭ7), whereas in 7 others, a 10-week HC was followed by a 6-week normal diet (HC-N). Renal endothelial function was assessed in vivo with electron-beam computed tomography, and renal tissue was then studied ex vivo using Western blot, real-time quantitative polymerase chain reaction, gelatin zymography, and immunostaining. HC-HC kidneys showed endothelial dysfunction, accompanied by increased intrarenal oxidative stress, inflammation, activation of the endothelin and transforming-growth factor-␤ systems, and decreased matrix metalloproteinase expression and activity. Accordingly, HC-HC kidneys showed increased collagen IV expression and fibrosis. A lipid-lowering dietary intervention reversed most of these changes. In conclusion, this study indicates that renal fibrosis in early atherosclerosis is a result of a simultaneous increase in extracellular matrix deposition and blunted matrix metalloproteinase-mediated degradation, overall promoting perivascular and tubulointerstitial fibrosis. Notably, many of these pathways may be reversible in hypercholesterolemia, and crucial targets could potentially be identified for early interventions to preserve the kidney. Key Words: kidney Ⅲ hypercholesterolemia Ⅲ fibrosis Ⅲ remodeling Ⅲ oxidative stress H ypercholesterolemia is a common cardiovascular risk factor. Approximately 50% of the middle-aged adult population has total cholesterol above desirable levels, 1 a strong, independent predictor of progression of atherosclerosis. 2 Dyslipidemia also often accompanies and aggravates early and advanced renal disease. 3,4 We have previously shown in a pig model that a 10-to 12-week diet-induced hypercholesterolemia, a risk factor for early atherosclerosis, elicited renal dysfunction, inflammation, and fibrosis, partly mediated by increased oxidative stress. [5][6][7][8] Increased oxidative stress may contribute to renal damage in hypercholesterolemia and atherosclerosis by virtue of augmented generation of reactive oxygen species (ROS) and oxidation of LDLs, 8 -12 which may induce endothelial dysfunction and activate redox-sensitive growth factors and cytokines. In addition, lipid accumulation or cellular damage can promote renal dysfunction, glomerular injury, and interstitial fibrosis. 13,14 A dynamic and complex process in which tissue growth is counterbalanced by degradation and removal preserves the normal structure of the kidney and may be partly modulated by endothelium-derived factors. Kidney disease and normal renal development are characterized by a high rate of extracellular matrix (ECM) turnover. Sev...

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Section: Discussionmentioning

confidence: 99%

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

et al. 2005

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“…This hypercholesterolemia might be triggered by the enhancement of albumin and TC production in the liver, resulting from hypoalbuminemia (17). Furthermore, it has been reported that hypercholesterolemia is a factor that underlies the progression of renal injury, as well as being a risk factor for arteriosclerosis (18), because the deposition and oxidization of plasma cholesterol in glomeruli and tubules induces the expression of transforming growth factor-b1 and thus accelerates renal injury (19,20). In SHC rats, the abnormality of cholesterol metabolism appeared at the same time as the onset of albuminuria, and this hypercholesterolemia may contribute partially to the pathogenesis and progression of renal injury.…”

Section: Discussionmentioning

confidence: 99%

Renal Protective Effect of Candesartan Cilexetil in Spontaneously Hypercholesterolemic Rats

Matsuo

Ishikawa

Ohta

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-Spontaneously hypercholesterolemic (SHC) rats exhibit hypercholesterolemia, proteinuria and focal glomerulosclerosis with age, and they finally die as a result of renal failure. In this study, the renoprotective effects of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, and enalapril, an angiotensin I converting enzyme inhibitor, were examined in SHC rats. Candesartan cilexetil (0.1 and 1 mg /kg) and enalapril (10 mg /kg) were administered orally to 10-week-old SHC rats for a 6-week period. Candesartan cilexetil (1 mg /kg) and enalapril (10 mg /kg) significantly inhibited proteinuria and hypercholesterolemia to a similar extent. In untreated 16-week-old SHC rats, glomerulosclerosis, basophilic change, cast formation and interstitial mononuclear cell infiltration were observed. Candesartan cilexetil (1 mg /kg) inhibited all of these histological changes. Enalapril inhibited glomerulosclerosis and cast formation. These results show that candesartan cilexetil and enalapril have renal protective effects in SHC rats. Thus, angiotensin II might play an important role in renal pathogenesis in a model of focal glomerulosclerosis with hypercholesterolemia.

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“…9 In vitro studies have demonstrated that LDL and oxidized LDL stimulate TGF-β1 gene expression in both human glomerular mesangial and epithelial cells. 10,11 Therefore, TGF-β1 appears to be an important mediator of lipid-induced mesangial matrix expansion as well as playing a key role in the pathogenesis of diabetic nephropathy. 4,[10][11][12] Finally, the uptake of modified LDL by macrophages has been reported to stimulate eicosanoid synthesis including thromboxanes and leukotrienes, leading to potentially deleterious alterations in intra-glomerular hemodynamics.…”

Section: Mechanisms Of Lipid-induced Renal Injury In the Glomerulusmentioning

confidence: 99%

“…10,11 Therefore, TGF-β1 appears to be an important mediator of lipid-induced mesangial matrix expansion as well as playing a key role in the pathogenesis of diabetic nephropathy. 4,[10][11][12] Finally, the uptake of modified LDL by macrophages has been reported to stimulate eicosanoid synthesis including thromboxanes and leukotrienes, leading to potentially deleterious alterations in intra-glomerular hemodynamics. 6 In this regard, dietary cholesterol supplementation in animals has been shown to result in an increase in efferent arteriole resistance and a subsequent elevation in intra-glomerular pressure.…”

Section: Mechanisms Of Lipid-induced Renal Injury In the Glomerulusmentioning

confidence: 99%

The study of dyslipidemia and its correlation with nephropathy in diabetes mellitus type 2 patients

Sisodia¹,

Gupta

Singh

2017

Int J Adv Med

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Background: Diabetic nephropathy is one of the most severe diabetic microangiopathies. The aim of this study was to evaluate the lipid abnormalities associated with different stages of proteinuria in type 2 diabetic patients.Methods: In this study 100 type 2 diabetic patients were subjected to detailed history, clinical examination, Serum lipid profile, urine albumin creatinine ratio and routine biochemical investigations.Results: Out of 100 patients were included in study, 41 patients were normoabluminuric, 37 patients were microalbuminuric and 22 patients were overt proteinuric. Most common dyslipidemia found in study is increased triglyceride (43%) followed by increased LDL (28). On comparing normoalbuminuric to overt proteinuric, a positive correlation found in increased triglyceride (P value < 0.001) and increases LDL (P value <0.001).Conclusions: Concluded that raised Triglyceride and LDL are associated with Diabetic Nephropathy.

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Oxidized LDL stimulates the expression of TGF-β and fibronectin in human glomerular epithelial cells

Cited by 83 publications

References 36 publications

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

Pathways of Renal Fibrosis and Modulation of Matrix Turnover in Experimental Hypercholesterolemia

Renal Protective Effect of Candesartan Cilexetil in Spontaneously Hypercholesterolemic Rats

The study of dyslipidemia and its correlation with nephropathy in diabetes mellitus type 2 patients

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