Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1−/− hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1−/− hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1−/− hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1−/− hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1+/+ cells, which was not the case in Cav1−/− cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells

Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1−/− hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1−/− hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1−/− hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1−/− hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1+/+ cells, which was not the case in Cav1−/− cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells

Dissociation between blood pressure reduction and fall in proteinuria in primary renal disease: a randomized double-blind trial

OBJECTIVEGuidelines recommend lower threshold and goal blood pressure (BP) for patients with proteinuria. BP reduction could be accompanied by a different fall in proteinuria depending of the antihypertensive drug. The objective was to compare proteinuria reduction when BP is lowered to the same level with different drugs.DESIGNProspective, randomized, double-blind, controlled trial.SETTING12 Spanish centres.PATIENTSA total of 119 patients with primary renal disease, blood pressure > 130/85 mmHg, proteinuria > 1 g/day, and creatinine clearance > or = 50 ml/min.INTERVENTIONAfter a 4-week run-in placebo period, patients were randomized to: atenolol 50 mg/day; trandolapril 2 mg/day; verapamil 240 mg/day or verapamil 180 + trandolapril 2 mg/day combination; forced double-dose titration was carried out at the 4th week. Treatment duration was 6 months.OUTCOME MEASURESChanges in BP, 24 h proteinuria, serum albumin and calcium.RESULTSBP was significantly reduced with the four treatments [SBP/DBP (mmHg]: atenolol 12.2/9.9; trandolapril 12.9/9.3; verapamil 8.2/7.9 and verapamil + trandolapril 13.6/11.3) without differences between them. A significant fall in proteinuria was seen in the trandolapril, 40.2% [95% confidence interval (CI) 24.3-56.2%], and verapamil + trandolapril groups, 48.5% (95% CI, 31.7-64.3%) accompanied with increases in serum albumin (trandolapril: from 3.86 +/- 0.64 to 4.03 +/- 0.67 g/dl; verapamil + trandolapril: from 4.15 +/- 0.58 to 4.40 +/- 0.51 g/dl).CONCLUSIONSIn patients with proteinuric primary renal disease, adequate dose titration of antihypertensive drugs may provide a substantial BP reduction. Only angiotensin-converting enzyme inhibitor (trandolapril) treatment, alone or better combined with verapamil, reduces proteinuria and increases serum albumin